Phase 1 of metabolism is concerned with functionalization, that is the introduction or exposure of functional groups on the chemical structure of a compound. This provides a 'handle' for phase 2 conjugating species with which to react with. Many xenobiotics are lipophilic and almost chemically inert (e.g. PAHs) so would not necessarily undergo a phase 2 reaction. Making them more chemically reactive would facilitate their excretion but also increases their chance of reacting with cellular macromolecules (e.g. proteins, DNA). There is a fine balance between producing a more reactive metabolite and conjugation reactions. There are two groups of enzymes in phase 1 - oxidoreductases and hydrolases. Oxidoreductases introduce an oxygen atom into or remove electrons from their substrates. The major oxidoreductase enzyme system is called the P450 monooxygenases. Other systems include flavin-containing monooxygenases (FMO), cyclooxygenases (COX) and monoamine oxidases (MAO). Hydrolases hydrolyse esters, amides, epoxides and glucuronides.
View original pathway at Reactome.
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Xie HJ, Yasar U, Lundgren S, Griskevicius L, Terelius Y, Hassan M, Rane A.; ''Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation.''; PubMedEurope PMCScholia
Lefèvre C, Bouadjar B, Ferrand V, Tadini G, Mégarbané A, Lathrop M, Prud'homme JF, Fischer J.; ''Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3.''; PubMedEurope PMCScholia
Kaiser R, Holmquist B, Hempel J, Vallee BL, Jörnvall H.; ''Class III human liver alcohol dehydrogenase: a novel structural type equidistantly related to the class I and class II enzymes.''; PubMedEurope PMCScholia
Gruenewald S, Wahl B, Bittner F, Hungeling H, Kanzow S, Kotthaus J, Schwering U, Mendel RR, Clement B.; ''The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.''; PubMedEurope PMCScholia
Badawi AF, Cavalieri EL, Rogan EG.; ''Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol.''; PubMedEurope PMCScholia
Yokoyama H, Baraona E, Lieber CS.; ''Molecular cloning of human class IV alcohol dehydrogenase cDNA.''; PubMedEurope PMCScholia
Guengerich FP.; ''Cytochrome P450s and other enzymes in drug metabolism and toxicity.''; PubMedEurope PMCScholia
Kaitaniemi S, Elovaara H, Grön K, Kidron H, Liukkonen J, Salminen T, Salmi M, Jalkanen S, Elima K.; ''The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase.''; PubMedEurope PMCScholia
Zeigler-Johnson C, Friebel T, Walker AH, Wang Y, Spangler E, Panossian S, Patacsil M, Aplenc R, Wein AJ, Malkowicz SB, Rebbeck TR.; ''CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer.''; PubMedEurope PMCScholia
Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, Forrest SM.; ''Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.''; PubMedEurope PMCScholia
Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF.; ''Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.''; PubMedEurope PMCScholia
Renaud S, de Lorgeril M.; ''Wine, alcohol, platelets, and the French paradox for coronary heart disease.''; PubMedEurope PMCScholia
Ishida H, Noshiro M, Okuda K, Coon MJ.; ''Purification and characterization of 7 alpha-hydroxy-4-cholesten-3-one 12 alpha-hydroxylase.''; PubMedEurope PMCScholia
Wu K, Knox R, Sun XZ, Joseph P, Jaiswal AK, Zhang D, Deng PS, Chen S.; ''Catalytic properties of NAD(P)H:quinone oxidoreductase-2 (NQO2), a dihydronicotinamide riboside dependent oxidoreductase.''; PubMedEurope PMCScholia
Guengerich FP, Kim DH, Iwasaki M.; ''Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects.''; PubMedEurope PMCScholia
Domanski TL, Finta C, Halpert JR, Zaphiropoulos PG.; ''cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450.''; PubMedEurope PMCScholia
Bour S, Daviaud D, Gres S, Lefort C, Prévot D, Zorzano A, Wabitsch M, Saulnier-Blache JS, Valet P, Carpéné C.; ''Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes.''; PubMedEurope PMCScholia
Li TK, Bosron WF, Dafeldecker WP, Lange LG, Vallee BL.; ''Isolation of pi-alcohol dehydrogenase of human liver: is it a determinant of alcoholism?''; PubMedEurope PMCScholia
Woods ST, Sadleir J, Downs T, Triantopoulos T, Headlam MJ, Tuckey RC.; ''Expression of catalytically active human cytochrome p450scc in Escherichia coli and mutagenesis of isoleucine-462.''; PubMedEurope PMCScholia
Knox RJ, Jenkins TC, Hobbs SM, Chen S, Melton RG, Burke PJ.; ''Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy.''; PubMedEurope PMCScholia
Schaupp CM, White CC, Merrill GF, Kavanagh TJ.; ''Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3.''; PubMedEurope PMCScholia
Zhao B, Bie J, Wang J, Marqueen SA, Ghosh S.; ''Identification of a novel intracellular cholesteryl ester hydrolase (carboxylesterase 3) in human macrophages: compensatory increase in its expression after carboxylesterase 1 silencing.''; PubMedEurope PMCScholia
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/PER-ARNT-SIM family of DNA binding proteins and controls the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1), one X-associated protein (AIP), and one p23 molecular chaperone protein (PTGES3). After ligand binding and activation, the AHR complex translocates to the nucleus, disassociates from the chaperone subunits, dimerises with the aryl hydrocarbon receptor nuclear translocator (ARNT) and transactivates target genes via binding to xenobiotic response elements (XREs) in their promoter regions. AHR targets genes of Phase I and Phase II metabolism, such as cytochrome P450 1A1 (CYP1A1), cytochorme P450 1B1 (CYP1B1), NAD(P)H:quinone oxidoreductase I (NQO1) and aldehyde dehydrogenase 3 (ALHD3A1). This is thought to be an organism's response to foreign chemical exposure and normally, foreign chemicals are made less reactive by the induction and therefore increased activity of these enzymes (Beischlag et al. 2008).
AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006).
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Trimethylamine (TMA) is present in the diet (in fish) but primarily formed in vivo from the breakdown of choline. It is N-oxidised by FMO3 in the liver, the major isoform active towards TMA, to form trimethylamine-N-oxide (TMAO). Trimethylaminuria (fish-odour syndrome) is a human genetic disorder characterised by an impaired ability to convert the malodourous TMA to the odourless N-oxide form TMAO (Higgins et al. 1972, Humbert et al. 1970, Treacy et al. 1998). L-carnitine is an abundant component of red meat and contains a trimethylamine structure similar to that of choline. Gut microbiota is able to produce TMAO from L-carnitine. If high levels of L-carnitine via high red meat intake or dietary supplements is achieved, Koeth et al. have shown the resultant TMAO produced in the gut can accelerate atherosclerosis in mice and increase the risk of cardiovascular disease (CVD) (Koeth et al. 2013).
Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973).
Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994).
Amine oxidase (flavin-containing) A (MAOA) catalyses the oxidative deamination of biogenic and dietary amines, the regulation of which is critical for mental state homeostasis. MAOA, located on the mitochondrial outer membrane and requiring FAD as cofactor (Weyler 1989), preferentially oxidises biogenic amines such as 5-hydroxytryptamine (5HT), dopamine, noradrenaline and adrenaline (latter three not shown here). 5HT is deaminated to 5-hydroxyindolacetaldehyde (5HIALD).
At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'H2O', and 1 molecule of '2-Phenylethylamine' are present. At the end of this reaction, 1 molecule of 'NH3', 1 molecule of 'H2O2', and 1 molecule of 'Phenylacetaldehyde' are present.
This reaction takes place in the 'mitochondrial outer membrane' and is mediated by the 'amine oxidase activity' of 'MAOB-FAD complex'.
Monoamine oxidases (MAOA and B), present in the outer mitochondrial membrane, catalyse the oxidation of biogenic amines, releasing hydrogen peroxide (H2O2). H2O2 produced during the oxidative deamination of these amines appears to be involved in the progress of neurodegenerative disorders such as Parkinson disease, presumably via oxidative damage to the mitochondrial membrane. MAOB (also MAOA but not show here), with FAD as cofactor, can deaminate tyramine (TYR), a naturally-occuring monoamine that can act as a catecholamine releasing agent (Pearce & Roth 1985).
Spermine oxidase (SMOX, PAOh1, SMO) is a polyamine oxidase flavoenzyme that catalyses the oxidation of spermine (SPN) to spermidine (SPM). It plays an important role in the regulation of endogenous polyamine intracellular concentration. Five different isozymes are produced by alternative splicing with isozyme 3 being the major isoform and possessing the highest affinity for spermine. It is highly inducible by specific antitumor polyamine analogues (Wang et al. 2001).
Acetylated spermidine (NASPM) is oxidised by the flavoenzyme polyamine oxidase (PAOX, with FAD as cofactor) to produce putrescine (PTCN). PAOX is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations (Vujcic et al. 2003).
Acetylated spermine (NASPN) is oxidised by the flavoenzyme polyamine oxidase (PAOX, woth FAD as cofactor) to produce spermidine (SPM). PAOX is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations (Vujcic et al. 2003).
The MEOS (microsomal ethanol oxidizing system) is an accessory pathway in the liver which increases in activity on chronic alcohol induction. The MEOS utilizes a cytochrome P450 which has since been deciphered to be CYP2E1, an ethanol-inducible form of P450. CYP2E1 also increases acetaldehyde formation and free radicals which can initiate lipid peroxidation. CYP2E1 can also activate many over-the-counter medicines and solvents to toxic metabolites and deplete retinoids resulting in their depletion and deletrious effects. This is because, being a cytochrome P450 and using NADPH and oxygen, it has the ability to biotransform drugs when it has been induced by ethanol.
Cholesterol, NADPH + H+, and O2 form 7alpha-cholesterol (5-cholesten-3beta, 7alpha-diol), NADP+,and H2O, in a reaction catalysed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic reticulum membrane. In the body, this enzyme is expressed only in liver, and its expression is tightly regulated at the level of transcription to determine the overall rate of bile acid and bile salt production (Noshiro et al. 1990).
Cholesterol 24-hydroxylase (CYP46A1), an enzyme associated with the ER membrane, catalyses the 24-hydroxylation of cholesterol (CHOL) to 24-hydroxycholesterol (24OH-CHOL). In the body, this enzyme is expressed predominantly in the brain and is thought to play a major role in cholesterol turnover there (Lund et al. 1999, Mast et al. 2003).
25-hydroxycholesterol (25OH-CHOL) is 7alpha-hydroxylated to cholest-5-ene-3beta,7alpha,25-triol (CHOL3b,7a,25TRIOL) by CYP7B1 (cytochrome P450 7B1) (Wu et al. 1999).
Cholesterol CHOL), NADPH + H+, and O2 react to form 27-hydroxycholesterol (27OH-CHOL), H2O, and NADP+, in the mitochondrial matrix, catalysed by CYP27A1. 27OH-CHOL is the most abundant oxysterol in human plasma. Its formation is thought to play a central role in the mobilization of CHOL from non-hepatic tissues (Cali et al. 1991).
Sterol 12alpha hydroxylase (CYP8B1), an enzyme associated with the endoplasmic reticulum membrane, catalyses the 12-alpha-hydroxylation of 7-Alpha-hydroxycholest-4-en-3-one (4CHOL7aOLONE) to 7-alpha,12-alpha-dihydroxycholest-4-en-3-one (4CHOL7a,12aDONE). While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterised, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterised rabbit homolog (Ishida et al. 1992).
24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1), located on the ER membrane, 7-alpha-hydroxylates 24-hydroxycholesterol (24OH-CHOL) to cholest-5-ene-3beta,7alpha,24-triol (CHOL7a,24(S)DIOL). In the body, expression of CYP39A1 is restricted to the liver and is involved in bile acid metabolism (Li-Hawkins et al. 2000).
The conversion of androstenedione (ANDST) to estrone (E1) is catalysed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane (Toda et al. 1990, Simpson et al. 1994).
20alpha,22beta-hydroxycholesterol (20a,22b-DHCHOL), NADPH + H+, and O2 react to form pregnenolone (PREG), isocaproaldehyde (ISCAL), NADP+ and H2O. This cleavage reaction is catalysed by CYP11A (P450scc) associated with the inner mitochondrial membrane (Strushkevich et al. 2011). PREG is substantially more hydrophilic than cholesterol (CHOL) and hydroxycholesterol (HCHOL) and is released into the mitochondrial matrix.
Sterol 12alpha hydroxylase (CYP8B1) catalyses the 12-alpha-hydroxylation of 4-cholesten-7alpha,24(S)-diol-3-one (4CHOL7a,24(S)DONE) to 4-cholesten-7-alpha,12-alpha,24(S)-triol-3-one (4CHOL7a,12a,24(S)TONE). While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterised, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterised rabbit homolog (Ishida et al. 1992).
Sterol 12alpha hydroxylase (CYP8B1), associated with the endoplasmic reticulum membrane, catalyses the 12-alpha-hydroxylation of 4-Cholesten-7alpha,27-diol-3-one (4CHOL7a,27DONE) to 4-Cholesten-7alpha,12alpha,27-triol-3-one. While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterised, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterised rabbit homolog (Ishida et al. 1992).
Progesterone, NAPDH + H+, and O2 react to form 11-deoxycorticosterone, NADP+ and H2O. This reaction is catalyzed by CYP21A2 associated with the endoplasmic reticulum membrane.
18-Hydroxycorticosterone and NADPH + H+ react to form aldosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
Corticosterone, NADPH + H+, and O2 react to form 18-hydroxycorticosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
Cytochrome P450 11B1, mitochondrial (CYP11B1) usually hydroxylates 11-deoxycortisol (11DCORT) to form cortisol (CORT). CYP11B1 is associated with the inner mitochondrial membrane. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor, melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
Cytochrome P450 11B2, mitochondrial (CYP11B2 aka aldosterone hydroxylase) is an enzyme necessary for aldosterone biosynthesis via corticosterone (CORST) and 18-hydroxycorticosterone (18HCORST). The 11-beta oxidation of 11-deoxycorticosterone (11DCORST) leads to corticosterone (CORST) and 18-hydroxylation of this leads to 18-hydroxycorticosterone (18HCORST). 18-oxidation of 18HCORST yields aldosterone.
Lanosterol 14-alpha demethylase (CYP51A1) catalyses oxidative C14-demethylation of lanosterol (LNSOL) to 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol (4,4DMCHOLtrienol). Although the reaction is annotated here as a single concerted event, studies with purified rat enzyme indicate that the methyl group is converted successively to an alcohol and an aldehyde before being released as formate (Stromstedt et al. 1996, Strushkevich et al. 2010).
To be functionally active, vitamin D3 (VD3) needs to be dihydroxylated. The first hydroxylation at position 25 is carried out by ER membrane-located vitamin D 25-hydroxylase (CYP2R1) in the liver, forming 25-hydroxyvitamin D (calcidiol, 25(OH)D) (Shinkyo et al. 2004, Cheng et al. 2003).
The second step in vitamin D activation requires hydroxylation of 25-hydroxyvitamin D (calcidiol, 25(OH)D) to 1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D). This conversion is mediated by 25-hydroxyvitamin D-1-alpha hydroxylase (CYP27B1), an outer mitochondrial membrane-resident protein (Zehnder et al. 2002, Fritsche et al. 2003, Sawada et al. 1999).
Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20OH-LTB4), catalysed by CYP4F2 primarily in human liver (Jin et al. 1998) and also by CYP4F3 (Kikuta et al. 1998).
CYP2S1 is a recently discovered cytochrome P450 enzyme on the basis of homology searches of databases and was found to be homologous to the CYP2 family of enzymes that are known to metabolize xenobiotics (Rylander et al. 2001). CYP2S1 is expressed in skin cells and is inducible by UV radiation, coal tar and all-trans-retinoic acid (atRA), the latter also serving as a substrate for the enzyme. Expression of CYP2S1 was significantly higher in psoriatic plaque than in normal skin. Psoriasis is a chronic hyperproliferative and inflammatory disorder.
CYP2A13 can also 7-hydroxylate coumarin. It shares a 93.5% identity with CYP2A6 in the amino acid sequence but it is only about one-tenth as active as CYP2A6 in catalyzing coumarin 7-hydroxylation.
CYP3A7 is only expressed in fetal liver and not in adults. It has lower biotransformation capability than other members of the CYP3A family such as 3A4 or 3A5 but possesses a similar broad specificity. CYP3A7 plays a major role in fetal steroid hydroxylation, an example being the 6beta-hydroxylation of testosterone.
Human CYP4F12 is involved in metabolism of endogenous compounds such as inflammatory mediators (arachidonic acid and prostaglandin H2) as well as xenobiotics like terfenadine (an antihistaminic drug) (Bylund et al. 2001). The omega-hydroxylation of arachidonic acid (ARA) is shown here to form 18-hydroxyarachidonic acid (18OH-ARA aka 18-HETE).
Paclitaxel (Taxol) is a naturally occurring member of the taxane family of antitumor drugs. It acts by stabilizing microtubules. Paclitaxel is inactivated in human liver by CYP2C8, which catalyzes 6alpha-hydroxylation of paclitaxel.
19-hydroxyprostaglandins E1 and E2 (19OH-PGE1 and 2) are major components of human seminal fluid. The initial step in their formation is the 19-hydroxylation of prostaglandin H1 and H2 (PGH1 and 2). CYP4F8 performs this initial conversion (Bylund et al. 1999, 2000). The example of PGH2 is used here.
Endogenous retinoic acids (RA) which play a role in gene regulation exist as either cis or trans isomers. While CYP26C1 can also hydroxylate the trans form, it is unique in 4-hydroxylating the 9-cis isomer of RA (9cRA) in vitro (Taimi et al. 2004). However, the importance of 9cRA as an endogenous retinoid outside of the pancreas has not been demonstrated.
Injury to the eye's surface provokes an inflammatory response, mediated, in part, by 12-hydroxyeicosanoids. CYP4B1 catalyses the 12-hydroxylation of arachidonic acid (ARA) to 12-HETE and 12-HETrE (12-hydroxy-5,8,10,14-eicosatetraenoic acid and 12-hydroxy-5,8,14-eicosatrienoic acid respectively). Both these metabolites possess potent inflammatory and angiogenic properties (Ashkar et al. 2004). The example of 12-HETE formation only is shown here.
Omeprazole is a potent long-acting inhibitor of gastric acid secretion by irreversible binding to the proton pump (H+,K+) ATPase in the gastric parietal cell. CYP2C19 is the major P450 which involved in 5-hydroxylation of omeprazole.
The CYP3A family are the most abundantly expressed P450s in human liver, accounting for around 50% of xenobiotic drug metabolism. CYP3A4 is the most abundant member of the family and possesses broad specificity to a range of xenobiotics. Loperamide (LOP), an antidiarrheal, is mainly metabolized to desmethylloperamide (DLOP) through the N-demethylation pathway. This initial N-demethylation is carried out by CYP3A4.
Catabolic inactivation of the active, hormonal form of vitamin D3 (1,25-dihydroxyvitamin D3, calcitriol, CTL) is initially carried out by 24-hydroxylation, mediated by CYP24A1 (1,25-dihydroxyvitamin D3 24-hydroxylase). The product formed is eventually transformed to calcitroic acid (CTLA), the major water-soluble metabolite that can be excreted in bile.
Cytochrome P450 1B1 (CYP1B1) can oxidise a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics as well as activating a range of procarcinogens. A specific substrate is the female sex hormone estradiol-17beta (EST17b) which is 4-hydroxylated to 4-hydroxyestradiol-17beta 4OH-EST17b) (Badawi et al. 2001).
CYP3A43 belongs to the cytochrome P450 3A family, of which CYP3A4 is the most active member in the biotransformation of xenobiotics. Testosterone (TEST) metabolites are a major determinant of prostate growth and differentiation. CYP3A43, which is expressed in the prostate, exhibits minor 6-beta-hydroxylation activity towards TEST suggesting CYP3A43 may be involved in the etiology of prostate cancer (Domanski et al. 2001, Zeigler-Johnson et al. 2004).
A novel cytochrome P450, CYP2U1, may play an important role in modulating the arachidonic acid (ARA) signaling pathway. It was discovered by searching the human EST database for homology to existing CYPs and subsequent cloning and expression to obtain the enzyme. CYP2U1 was found to be highly expressed in the thymus and the brain (cerebellum) and found to metabolise ARA to 19-hydroxy-ARA (19HETE) and 20-hydroxy-ARA (20HETE). It is thought that CYP2U1 plays an important physiological role in fatty acid signaling processes in both the cerebellum and thymus (Chuang et al. 1994). The omega-hydroxylation (19) example is described here.
Long-chain 3-hydroxy fatty acids (3OHFAs) are omega-hydroxylated to form 3-hydroxydicarboxylic acid (3OHDCAs) precursors in human liver. These products may be implicated in pathological states where fatty acid mobilzation or impairment of mitochondrial fatty acid beta-oxidation increases 3-OHFA levels. CYP4A11, an orphan P450, has been shown to 18- and 16-hydroxylate 3-hydroxystearate and 3-hydroxypalmitate (3OH-PALM) respectively to omega-hydroxylated precursors; the latter is shown here (Dhar et al. 2008).
CYP2D6 (debrisoquine 4-hydroxylase) has a wide substrate specificity and is an important cytochrme P450 in drug metabolism. It has extensive genetic polymorphism (called the debrisoquine/sparteine oxidation polymorphism) that influences its expression and function.The polymorphism is responsible for populations being poor metabolizers (PM) or extensive metabolizers (EM, normal). Approximately 10% of Caucasians and less than 1% of Asians lack the CYP2D6 protein because of two null alleles which do not encode the functional product. Further polymorphisms discovered recently have identified ultrarapid metabolizers (PM) (alleles with multiple gene copies) and intermediate metabolizers (IM) (deficiency in their metabolism capacity) (Zanger UM et al, 2004).
CYP2W1 is a so-called "ophan P450", a cytochrome P450 enzyme which has no defined function or endogenous/xenobiotic substrates. CYP2W1 has recently been shown to be selectively expressed in some forms of cancers and, with the low expression in normal tissues, could be rendered as a possible drug target during cancer therapy (Yoshioka et al. 2006). CYP2W1 can bioactivate several procarcinogens but at lower levels than other P450s. CYP2W1 also shows monooxygenase activity towards the pigment indole (INDOL), an ingredient of perfumes and coal tar.
Activation of phospholipases releases free arachidonic acid (ARA) from phospholipid bilayers which can then be metabolised to biologically active eicosanoids (signaling molecules which exert effects in inflammation and immunity). The cytochrome P450 enzyme CYP2J2 (arachidonic acid epoxygenase) is mainly expressed in human heart and can metabolise ARA to epoxyeicosatrienoic acid (EET). Four cis-EETs can be produced: 5,6-, 8,9-, 11,12- and 14,15-EET. Each of these can be formed as the R,S or the S,R enantiomer (Zeldin DC, 2001). The most abundant regioisomer in human heart is 14,15-EET although 11,12-EET possesses the most potent anti-inflammatory effect (Wu et al. 1996).
Tolbutamide is an oral hypoglycemic agent whose action is terminated by hydroxylation of the tolylsulfonyl methyl moiety. The reaction is catalyzed by CYP2C9.
Cyclophosphamide (CPA) is an alkylating agent used in cancer chemotherapy and an immunosuppressant. CYP2B6 converts CPA to the active metabolite 4-hydroxy-CPA.
Phenytoin is a widely used anti-epileptic drug which can be hydroxylated by several P450s including CYP2C18 to its major metabolite, (5-(4-hydroxyphenyl)-phenylhydantoin (HPPH).
3-methylindole (3MI) is a fermentation product of tryptophan. It is usually formed in the rumen of goats and cattle and in the large intestine of humans. CYP2F1 shows the highest activity towards the dehydrogenation of 3MI to form a methylene imine-reactive intermediate.
Retinoic acid (RA) is a biologically active analogue of vitamin A (retinol). RA plays an important role in regulating cell growth and differentiation.CYP26A1 is involved in the metabolic breakdown of RA by 4-hydroxylation. CYP26A1-mediated 4-hydroxylation is specific for all-trans-RA but not for the isomers 13-cis-RA and 9-cis-RA (Sonneveld et al. 1998). CYP26B1 can also deactivate all-trans-retinoic acid by 4-hydroxylation. High expression levels in the cerebellum and pons of human brain suggests a protective role of specific tissues against retinoid damage (White et al. 2000).
Aflatoxins are produced by the fungal molds Aspergillus flavus and Aspergillus parasiticus. Dietary contamination accounts for adverse health problems including liver cancer therby classifying aflatoxins as Group 1 carcinogens in humans. The B1 form of aflatoxin (AFB1) is especially carcinogenic in a number of species including humans. AFB1 requires microsomal oxidation to produce epoxides which are the cause of their toxic and carcinogenic effects. In humans, both CYP3A4 and CYP3A5 are able to produce epoxide stereoisomers of AFB1, the most potent being aflatoxin B1 exo-8,9-oxide (AFXBO) (Gallagher et al. 1996).
Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20OH-LTB4). This deactivation can be carried out by CYP4F3 in addition to CYP4F2 (Kikuta et al. 1998).
Tamoxifen (TAM) is an antiestrogen and currently used extensively for breast cancer therapy. FMOs, especially FMO1 can N-oxidze TAM to tamoxifen N-oxide (TNO). TNO can be reduced back to TAM by the P450 system. TNO appears to be just as potent as TAM but with fewer side-effects so this metabolic cycling could play a part in the use of TNO in the treatment of breast cancer.
Methimazole is a drug used to treat hyperthyroidism, a condition arising when the thyroid gland is producing too much thyroid hormone. FMO2 is able to the S-oxidized form of methimazole.
Cytosolic acetaldehyde crosses the mitochondrial inner membrane and enters the mitochondrial matrix. Physiological studies have provided indirect evidence for acetaldehyde uptake by mitochondria (Lemasters 2007) but its molecular mechanism is unknown.
ACSS1 (acyl-CoA synthetase short-chain family member 1) in the mitochondrial matrix catalyzes the reaction of acetate, coenzyme A, and ATP to form acetyl-CoA, AMP, and pyrophosphate (Schwer et al. 2006).
Cytochrome P450 4F22 (CYP4F22) is thought to 20-hydroxylate trioxilin A3 (TrXA3), an intermediary metabolite from the 12(R)-lipoxygenase pathway. This pathway is implicated in proliferative skin diseases. The major products of arachidonic acid in keratinocytes are 12- and 15-HETE which undergo biotransformation to products involved in skin hydration. CYP4F22 mutations can lead to autosomal recessive congenital ichthyosis (ARCI) (Lefevre et al. 2006).
Esterases contribute to the metabolism of ~10% of therapeutic drugs. Esterases hydrolyse compounds that contain ester, amide, and thioester bonds, which result in prodrug activation or detoxification. Arylacetamide deacetylase (AADAC) is involved in the hydrolysis of flutamide, phenacetin, and rifamycins. AADAC is associated with adverse drug reactions as hydrolytic metabolites of flutamide and phenacetin are associated with hepatotoxicity and nephrotoxicity/hematotoxicity, respectively. Phenacetin (PHEN) is a mild analgesic/antipyretic drug, widely used from its introduction in 1887 until its ban in 1983. It was banned because of its adverse effects, which include increased risk of certain cancers and kidney damage. It is metabolised into paracetamol, which replaced it as an over-the-counter medication following the ban on PHEN. AADAC hydrolyses PHEN to the p-phenetidine metabolite which is a nephrotoxicant (Watanabe et al. 2010, Fukami & Yokoi 2012).
Alcohol dehydrogenase class-3 (ADH5) is a cytosolic dimeric enzyme that binds 2 Zn2+ per subunit. It is very ineffective in oxidising ethanol, but it readily catalyses the oxidation of S-(hydroxymethyl) glutathione (S-HMGSH) to S-formylglutathione (S-FGSH) (Kaiser et al. 1988, Julia et al. 1988) as well as the oxidation of long-chain primary alcohols (not shown here).
Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in cancer chemo-resistance by oxidising activated forms of oxazaphosphorine drugs such as 4-hydroperoxycyclophosphamide (4HPCP) to the inactive metabolite carboxy-phosphamide (CXPA) (Moreb et al. 2007, Parajuli et al. 2014).
Cocaine (COCN) is an addictive, psychoactive alkaloid that is primarily inactivated by hydrolysis to benzoylecgonine (BEG), the major urinary metabolite of the drug. Human liver carboxylesterases 1 and 2 (CES1 and 2), located in the ER lumen, are involved in the detoxification of xenobiotics and can hydrolyse COCN to BEG (Brzezinski et al. 1994, Pindel et al. 1997). CES1 is functional as a homotrimer or homohexamer (Bencharit et al. 2003) whereas CES2 is monomeric.
Microsomal epoxide hydrolase 1 (EPHX1) is involved in the metabolism of many potentially carcinogenic and/or genotoxic epoxides, such as those derived from the oxidation of polyaromatic hydrocarbons. It catalyses the hydration of arene and aliphatic epoxides to less reactive and more water-soluble dihydrodiols. An example substrate is epoxide benzo(a)pyrene 4,5-oxide (BaP4,5O), hydrated to benzo(a)pyrene 4,5-dihydrodiol (BaP4,5DHD) (Hosagrahara et al. 2004, Fretland & Omiecinski 2000).
Ethanol-induced organ damage is attributed to its toxic metabolite acetaldehyde (CH3CHO) therefore metabolism and elimination of this metabolite is important for cellular defence. Mitochondrial ALDH1B1 is one of several human ALDHs that can oxidise CH3CHO to acetic acid (CH3COOH) (Stagos et al. 2010). ALDH1B1 is thought to function as a homotetramer.
Amiloride-sensitive, copper-containing amine oxidase (AOC1) can catalyse the oxidative deamination of diamines, particularly histamine (Hist) (McGrath et al. 2009). Histamine is involved in allergic and immune responses.
Retina-specific copper amine oxidase (AOC2) is present on the cell surface of most cells but especially retinal cells. It is classed as a semicarbazide-sensitive amine oxidase (SSAO) and catalyses the oxidative deamination of aromatic amines such as tyramine (TYR, shown here), 2-phenylethylamine and tryptamine (Kaitaniemi et al. 2009, Bour et al. 2007). Overexpression of AOC2 could result in tissue destruction seen in ocular pathologies.
Membrane primary amine oxidase (AOC3, aka vascular adhesion protein 1, VAP-1) is a membrane-bound, dimeric enzyme that can catalyse the oxidative deamination of primary amines such as benzylamine (BZAM) and methyalmine to their respective aldehydes (Kaitaniemi et al. 2009, Bour et al. 2007). It is widely expressed with highest expression in peripheral lymph nodes, hepatic endothelia, appendix, lung and small intestine (Smith et al. 1998).
Valacyclovir (VACV) is the 5'-valyl ester prodrug of acyclovir (ACV), an effective anti-herpetic drug. Systemic bioavailability of ACV in humans is up to five times higher when administered orally as the prodrug. After intestinal absorption, valacyclovir hydrolase (BPHL) mediates the rapid and complete hydrolysis to VACV to ACV (Kim et al. 2003, Lai et al. 2008). The subcellular location of human BPHL is unknown but rat Bhpl localises to the mitochondrial membrane (Kim et al. 2003).
Carboxymethylenebutenolidase homolog (CMBL) is a cytosolic hydrolase enzyme present in liver and intestine. It is able to hydrolyse medoxomil-type pro-drugs to their pharmacologically active metabolites. Olmesartan medoxomil (OM) is an angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. It is hydrolysed by CMBL to its active metabolite olmesartan (OLMS) (Ishizuka et al 2010). True physiological substrates of CMBL remain unknown.
The main physiological function of normal retinal photoreceptor epithelial (RPE) cells is to import polyunsaturated fatty acids (PUFAs) from the bloodstream and to recycle them to maintain lipid homeostasis in photoreceptors. CYP4 enzymes are microsomal fatty acid omega-hydroxylases that function to degrade cellular lipids. CYP4V2 is present in epithelial cells of the retina and cornea, localised to the endoplasmic reticulum membrane and can hydroxylate PUFAs to their respective omega-hydroxylated products. Docosahexaenoic acid (DHA), which is found at high concentrations in the eye, is a C22 PUFA which is hydroxylated to omega-hydroxy-DHA (Nakano et al. 2009, 2012). Defects in CYP4V2 can cause Bietti crystalline corneoretinal dystrophy (BCD; MIM:210370), an ocular disease characterised by retinal degeneration and marginal corneal dystrophy resulting in progressive night blindness and constriction of the visual field. A typical feature is multiple glistening intraretinal crystals scattered over the fundus (Li et al. 2004, Nakano et al. 2012).
ALDH1A1 (aldehyde dehydrogenase) in the cytosol catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ (Inoue et al. 1979). The active form of the enzyme is a tetramer (Ni et al. 1999).
Cytosolic alcohol dehydrogenase catalyzes the reaction of ethanol and NAD+ to form acetaldehyde and NADH + H+. The active form of the enzyme is a dimer with one zinc ion bound to each protein subunit. In the body, alcohol dehydrogenase is present in the liver, kidney, lung and gastric mucosa.
Six genes encode proteins active in ethanol oxidation: ADH1A, ADH1B, ADH1C, ADH4, ADH6, and ADH7 (Lange et al. 1976; Yin et al. 1985; Li et al. 1978; Bosron et al. 1979; Moreno and Pares 1991; Yokoyama et al. 1994; Chen and Yoshida 1991). ADH1A, B and C proteins can associate to form homodimers or heterodimers; ADH4, 6, and 7 proteins each form homodimers. Expression of ADH1A, B and C is developmentally regulated: ADH1A protein is abundant in the fetus, but expressed only at low levels in adulthood, when ADH1B and C proteins are abundant (Edenberg 2000). The various dimers differ substantially in the efficiency with which they oxidize ethanol. The ADH1B homodimer and heterodimers containing at least one 1B monomer are the most active towards ethanol (Yin et al. 1985). In addition, common polymorphic variants of ADH1B and C proteins differ substantially in this respect (Murray and Price 1972).
ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ (Greenfield and Pietruszko 1977; Hempel et al. 1985). The active form of the enzyme is a tetramer (Ni et al. 1999).
Cytosolic ACSS2 (acetyl-coenzyme A synthetase) catalyzes the reaction of acetate, coenzyme A, and ATP to form acetyl-CoA, AMP, and pyrophosphate (Luong et al. 2000).
CYP2E1 can catalyze the oxidation of the vinyl halide vinyl chloride to the epoxide 2-chloroethylene oxide. The epoxide is very unstable and rearranges quickly to 2-chloroacetaldehyde. Both these products can interact with DNA and proteins.
Heterocyclic and aromatic amines require metabolic activation to convert them to genotoxic metabolites.The initial step is N-hydroxylation and cytochrome P450 1A2 can carry out the catalysis.
N-acetyl-p-benzoquinone imine (NAPQI) is the reactive intermediate of the analgesic and antipyretic, acetaminophen (INN, paracetamol). At usual doses, NAPQI is quickly detoxified by conjugation but in overdose situations, NAPQI is extremely toxic to liver tissue.
Benzene is an occupational and environmental toxicant and is implicated in myelogenous leukemia. For toxicity to occur, benzene is oxidised to phenol and subsequently to catechol and hydroquinone. CYP2E1 is the enzyme responsible for oxidation of benzene to phenol.
Caffeine is one of the world's most frequently consumed xenobiotic. The major source of caffeine comes from tea and coffee. Caffeine is extensively metabolized in humans with at least 17 metabolites formed in its biotransformation. CYP1A2 is a prominent enzyme in the formation of an important metabolite of caffeine (paraxanthine) by N3-demethylation.
Carbon tetrachloride (CCl4) has been widely used as a dry-cleaning agent, in fire extinguishers and in the manufacture of other halogenated hydrocarbons. At toxic doses, CCl4 exposure can damage the liver and kidneys. This toxicity results from CYP2E1-dependant reduction of CCl4 to the reactive trichloromethyl radical (CCl3.).
The 7-hydroxylation of coumarin is used as an assay of P450 activity in animal and human liver microsomes. CYP2A6 is the major coumarin 7-hydroxylase in human liver.
At the beginning of this reaction, 1 molecule of 'H+', 1 molecule of 'Dextromethorphan', 1 molecule of 'Oxygen', and 1 molecule of 'NADPH' are present. At the end of this reaction, 1 molecule of 'NADP+', 1 molecule of 'Dextrorphan', 1 molecule of 'Formaldehyde', and 1 molecule of 'H2O' are present.
This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 2D6 '.
Dodecanoic acid (DDCX aka lauric acid) is a medium-chain fatty acid which serves as a model substrate for studying the CYP4A gene subfamily of cytochrome P450s. CYP4A11 and CYP2E1 are the principal isozymes involved in omega-hydroxylation and omega-1 hydroxylation respectively of DDCX.
A simple example of epoxidation is the oxidation of an alkene (olefin) to the epoxide (oxirane), catalysed by CYP1A1. Even the simplest of epoxides (ethylene oxide) can react with DNA and amino groups in a protein.
The volatile anesthetic halothane can undergo CYP2E1-catalyzed oxidation to form a reactive intermediate which can acetylate liver proteins. These proteins can then stimulate an immune reaction that mediates severe hepatic necrosis ("halothane hepatitis").
NADPH-cytochrome P450 reductase (POR) (Shephard et al. 1992) and cytochrome-b5 and NADH-b5 reductase play important roles in cytochrome P450-mediated drug metabolism (Gan et al. 2009). POR can transfer electrons to many naturally occurring electron acceptors, including cytochrome P450 enzymes where it transfers the electrons from NADPH into the P450 catalytic cycle (Elmore & Porter 2002). The P450 catalytic cycle describes the transitional mechanistic steps by which P450s bind a substrate, act upon it and finally release the product, returning P450s to their initial state (see mini-review Guengerich 2007).
Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007).
Thromboxane synthase (TBXAS1) aka CYP5A1 mediates the isomerisation of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2) (Miyata et al. 2001, Chevalier et al. 2001). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH.
Mitochondrial amidoxime-reducing components 1 and 2 (MARC1 and 2) are Mo-molybdopterin (Mo-MPT) cofactor-dependent, outer mitochondrial membrane-associated enzymes capable of reducing N-hydroxylated prodrugs and N-hydroxy-L-arginine (NOHA) and N-hydroxy-N-methyl-L-arginine (NHAM) into L-arginine and N(delta)-methyl-L-arginine, respectively. They are components of an N-hydroxylated prodrug-converting complex, also containing cytochrome b5 (CYB5B) and NADH cytochrome b5 reductase 3 (CYB5R3) (Jakobs et al. 2014, Gruenewald et al. 2008, Ott et al. 2014, 2015). The reduction of NOHA is described in this reaction.
Quinone reductases 1 and 2 (NQO1 and NQO2) comprise the mammalian quinone reductase family of enzymes responsible for performing FAD-mediated reductions of quinone substrates. In contrast to NQO1, which uses NADPH as a co-substrate, NQO2 uses a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide (RFDHN). NQO2 is active in dimeric form, binding one FAD group per subunit (Wu et al. 1997). NQO2 can transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage (Celli et al. 2006, Knox et al. 2000).
Melatonin (MLT) has antioxidant effects and is able to bind NQO2, inhibiting its activity. Inhibition of NQO2 may lead to protection of cells against the production of highly reactive species (Calamini et al. 2008). Resveratrol is a phyto-polyphenol that is present in grapes and in significant amounts in grape juice and wines, particularly red wine. Resveratrol was found to be an anti-oxidant and a cancer chemopreventive agent (Jang et al. 1997). Its presence in red wine was also suggested to have cardioprotective effects, the so-called “French paradox�; an observation of lower incidence of cardiovascular disease in some French regions where red wine and saturated fats are consumed in greater quantities than in the US (Renaud & de Lorgeril 1992, Bradamante et al. 2004). The highest affinity target of resveratrol is NQO2. By inhibiting NQO2, resveratrol may protect cells against reactive intermediates and eventually cancer (Buryanovskyy et al. 2004, St John et al. 2013).
The anthracycline doxorubicin (DOX, adriamycin) is a widely-used chemotherapeutic agent effective against a broad range of malignant neoplasms, including blood cancers, carcinomas, and sarcomas. Its use is dose-limited by off-target complications, namely cardiomyopathies. Doxorubicinol (DOXOL, adriamycinol), an alcohol metabolite of doxorubicin, has been implicated in the cardiotoxicity observed in doxorubicin-treated patients (Olson et al. 1998). In a mouse model, carbonyl reductase [NADPH] 3 (Cbr3) is able to catalyse the NADPH-dependent two-electron reduction of DOX to DOXOL but at a much lower efficiency than its well-characterised family member Cbr1 (Schaupp et al. 2015). Naturally occurring variants of human CBR3 can significantly alter anthracycline metabolism (Bains et al. 2010). Inhibition of CBRs may provide protection from doxorubicinol cardiotoxicity.
In macrophage foam cells, the hydrolysis of cholesteryl esters (CHESTs) is the rate-limiting step in the removal of free cholesterol (CHOL) from these cells. CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles. Accumulation of CHESTs in macrophage foam cells is key to atherosclerotic plaque formation and occurs as a result of an imbalance between CHOL influx and efflux pathways. The main hydrolase that hydrolyses CE in macrophages is neutral cholesterol ester hydrolase 1 (NCEH1). Carboxylesterases (CESs), usually involved in the hydrolysis of drugs, can also hydrolyse CHESTs with CES1 responsible for >70% of the total CES hydrolytic activity in macrophages, thus playing an important antiatherogenic role. CES1 knockdown studies reveal a compensatory increase in the expression of CES3, expressed at <30% of the level of CES1 in human macrophages, which restores intracellular CHEST hydrolytic activity and CHOL efflux (Zhao et al. 2012). Human CES3 isoproteins are predicted to be either secreted or retained in the cytosol (Holmes et al. 2010) but the exact location is currently unknown.
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AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006).
dehydrogenase
complexAnnotated Interactions
This reaction takes place in the 'mitochondrial outer membrane' and is mediated by the 'amine oxidase activity' of 'MAOB-FAD complex'.
AFB1 requires microsomal oxidation to produce epoxides which are the cause of their toxic and carcinogenic effects. In humans, both CYP3A4 and CYP3A5 are able to produce epoxide stereoisomers of AFB1, the most potent being aflatoxin B1 exo-8,9-oxide (AFXBO) (Gallagher et al. 1996).
Six genes encode proteins active in ethanol oxidation: ADH1A, ADH1B, ADH1C, ADH4, ADH6, and ADH7 (Lange et al. 1976; Yin et al. 1985; Li et al. 1978; Bosron et al. 1979; Moreno and Pares 1991; Yokoyama et al. 1994; Chen and Yoshida 1991). ADH1A, B and C proteins can associate to form homodimers or heterodimers; ADH4, 6, and 7 proteins each form homodimers. Expression of ADH1A, B and C is developmentally regulated: ADH1A protein is abundant in the fetus, but expressed only at low levels in adulthood, when ADH1B and C proteins are abundant (Edenberg 2000). The various dimers differ substantially in the efficiency with which they oxidize ethanol. The ADH1B homodimer and heterodimers containing at least one 1B monomer are the most active towards ethanol (Yin et al. 1985). In addition, common polymorphic variants of ADH1B and C proteins differ substantially in this respect (Murray and Price 1972).
This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 2D6 '.
Melatonin (MLT) has antioxidant effects and is able to bind NQO2, inhibiting its activity. Inhibition of NQO2 may lead to protection of cells against the production of highly reactive species (Calamini et al. 2008). Resveratrol is a phyto-polyphenol that is present in grapes and in significant amounts in grape juice and wines, particularly red wine. Resveratrol was found to be an anti-oxidant and a cancer chemopreventive agent (Jang et al. 1997). Its presence in red wine was also suggested to have cardioprotective effects, the so-called “French paradox�; an observation of lower incidence of cardiovascular disease in some French regions where red wine and saturated fats are consumed in greater quantities than in the US (Renaud & de Lorgeril 1992, Bradamante et al. 2004). The highest affinity target of resveratrol is NQO2. By inhibiting NQO2, resveratrol may protect cells against reactive intermediates and eventually cancer (Buryanovskyy et al. 2004, St John et al. 2013).
dehydrogenase
complex