Category:Drug-metabolizing enzymes

A drug-metabolizing enzyme is one of the enzymes by which the body chemically transforms a medicine, after it has been taken, into something the body can use, inactivate, and ultimately excrete. The largest and most important family of these enzymes carries a name taken directly from a laboratory measurement. In the early 1960s, working at Osaka University, Tsuneo Omura and Ryo Sato studied a pigment in the microsomal fraction of liver cells and found that when it was chemically reduced and allowed to bind carbon monoxide it absorbed light sharply at a wavelength of 450 nanometres. They named the pigment for that absorption peak, and cytochrome P-450 has been called that ever since.^[1] This category collects the wiki's reference pages for the cytochromes P450 and for the other enzyme families that share their work.

The body does not, at the molecular level, distinguish a medicine from any other foreign organic chemical: a plant alkaloid, an industrial solvent, a combustion product are all, to the liver, the same kind of problem. The general term for such a substance is a xenobiotic, and the same enzyme systems process all of them. Pharmacologists describe that processing in two stages.^[2] Phase I reactions, principally oxidation but also reduction and hydrolysis, introduce or expose a chemically reactive group on the molecule. Phase II reactions, the conjugations, attach a bulky water-soluble group, glucuronic acid, sulfate, glutathione, or an acetyl group, to that reactive handle, producing a metabolite polar enough to leave the body in bile or urine. The two phases usually run in sequence: phase I prepares the molecule, phase II finishes it.

The phase-I oxidations are dominated by the cytochromes P450, a multigene family of heme-containing enzymes classified, by the homology of their amino-acid sequences, into families and subfamilies; in human medicine the CYP1, CYP2, and CYP3 groups carry most of the load.^[3] A cytochrome P450 does not act alone: it is the terminal oxidase of a small electron-transport assembly, the mixed-function oxidase or monooxygenase system, which draws electrons from NADPH through a flavoprotein partner, NADPH-cytochrome P450 reductase, and inserts one atom of molecular oxygen into the substrate while the other atom is reduced to water.^[2] The phase-II conjugations are carried out by a separate set of enzyme families: the UDP-glucuronosyltransferases, the sulfotransferases, the glutathione S-transferases, the N-acetyltransferases, and others. The eleven pages collected here cover both phases: eight cytochromes P450, and three phase-II and related enzymes.

A drug-metabolizing enzyme is usually described as part of the body's detoxification machinery, and most of the time the description holds: the metabolite is less active than the medicine, and the body is rid of it. But the same chemistry that inactivates one molecule can activate another. When a phase-I oxidation places its reactive group onto the wrong kind of substrate, the product is not a harmless handle for conjugation but a reactive, electrophilic species that binds to DNA and protein. This is metabolic activation, or bioactivation, and it is the molecular basis of a large part of chemical carcinogenesis.^[2] The recognition that foreign substances could cause disease in this way is older than the enzymology that explains it: in 1775 the London surgeon Percival Pott traced the scrotal cancers he saw in chimney sweeps to the soot of their trade, the first clear account of an environmental cause of human cancer.^[4] Two centuries later the mechanism was filled in. The polycyclic aromatic hydrocarbons of soot and tobacco smoke are activated to DNA-binding carcinogens by CYP1A enzymes; aflatoxin is activated by CYP3A4; the nitrosamines by CYP2E1. The same enzyme that safely clears a prescribed medicine can, presented with a different substrate, manufacture a carcinogen. Whether an enzyme detoxifies or activates a given chemical is a property of the specific pairing, and individual susceptibility to chemical injury depends in part on the balance between the activating cytochromes P450 and the detoxifying conjugating enzymes.^[2]

This balance, and the enzymes that strike it, are not the same in every person. Drug-metabolizing enzymes vary in activity from one individual to the next, partly through inherited genetic variation, partly through induction and inhibition by diet, by other medicines, by tobacco smoke, and by disease. Two patients given the same dose of the same medicine may therefore reach very different blood concentrations of it. That variation is the subject of pharmacogenomics, and it is the reason this wiki maintains a dedicated reference page for each drug-metabolizing enzyme of clinical importance.

Cytochrome P450 (CYP) enzymes, the hemoprotein monooxygenases responsible for the majority of phase-I oxidative drug metabolism:

• CYP1A2 (caffeine probe; clozapine, olanzapine, theophylline, tizanidine; the tobacco-smoke induction story)
• CYP2B6 (efavirenz, methadone, bupropion, cyclophosphamide bioactivation)
• CYP2C8 (paclitaxel, repaglinide, the glitazones; the gemfibrozil interaction)
• CYP2C9 (warfarin, phenytoin, NSAIDs, sulfonylureas)
• CYP2C19 (clopidogrel, proton pump inhibitors, several SSRIs, voriconazole)
• CYP2D6 (codeine and tramadol activation, tricyclic antidepressants, many antipsychotics, metoprolol, tamoxifen)
• CYP2E1 (ethanol, acetaminophen bioactivation, the halogenated anesthetics)
• CYP3A4 (the single most clinically consequential drug-metabolizing enzyme; roughly half of all medicines in clinical use)

Phase-II and other non-CYP enzymes:

• UGT1A1 (UDP-glucuronosyltransferase; bilirubin, irinotecan, atazanavir)
• TPMT (thiopurine S-methyltransferase; azathioprine, mercaptopurine, thioguanine)
• NUDT15 (nudix hydrolase; the parallel thiopurine-safety gene with a complementary ancestry distribution to TPMT)

The boundary of this category is "enzyme that metabolizes medicines," not "every gene relevant to pharmacogenomics." Drug transporters (such as SLCO1B1 and ABCB1) move medicines across membranes rather than chemically transforming them, and they are collected separately. The pharmacogenomically important non-enzyme variant loci (such as the HLA-B alleles that govern severe hypersensitivity reactions) are likewise collected separately. Some loci sit at the edge of the boundary: VKORC1, the warfarin target, is a reductase enzyme and may be indexed here when its page is built; G6PD and DPYD are enzymes and belong here when built.

Each enzyme page follows a common structure: a history-first opening, tissue distribution, the substrate spectrum with a sortable substrate table, phenotype categories, major genetic variants, inhibitors, inducers, clinical implications, and authoritative external resources. Each page is also the human-readable companion to the machine-level pk_inhibit_via_<ENZYME> and pk_induce_via_<ENZYME> interaction edges in the wiki's pharmacogenomic interaction layer.

These pages currently live as drafting sandboxes under the Pharmacopedia: project namespace (titled Pharmacogenomics sandbox/Enzyme <NAME>); their permanent home will be the dedicated Enzyme: namespace once it is registered. The closely related transporter, variant, and phenotype pages will live under Transporter:, Variant:, and Phenotype: respectively.