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Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics
William E. Evans and Mary V. Relling
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Supplementary Material
| | Supplemental Table 1. Genetic polymorphisms of human drug-metabolizing enzymes and transporters. | | | Enzyme | Substrates | Consequences of polymorphism for drug effects | Reference | | | | | | | Phase I enzymes | | | | CYP1A1 | Benzo(a)pyrene, phenacetin | Not yet elucidated | (1) | | | CYP1A2 | Acetaminophen, amonafide, caffeine, paraxanthine, ethoxyresorufin, propranolol, fluvoxamine | Not yet elucidated | (2) | | | CYP1B1 | Estrogen metabolites | Not yet elucidated | (3) | | | CYP2A6 | Coumarin, nicotine, halothane | Cigarette addiction | (4) | | | CYP2B6 | Cyclophosphamide, aflatoxin, mephenytoin | Not yet elucidated | (5) | | | CYP2C8 | Retinoic acid, paclitaxel | Not yet elucidated | | | | CYP2C9 | Tolbutamide, warfarin, phenytoin, nonsteroidal anti-inflammatories | Anticoagulant effect of warfarin | (6) | | | CYP2C19 | Mephenytoin, omeprazole, hexobarbital, mephobarbital, propranolol, proguanil, phenytoin | Peptic ulcer cure rates with omeprazole | (7) | | | CYP2D6 | Beta blockers, antidepressants, antipsychotics, codeine, debrisoquin, dextromethorphan, encainide, flecainide, guanoxan, methoxyamphetamine, N-propylajmaline, perhexiline, phenacetin, phenformin, propafenone, sparteine | Tardive dyskinesia from antipsychotics, narcotic side effects, efficacy, and dependence, imipramine dose requirement, beta blocker effect | (8, 9) | | | | | |
Supplemental Table 1. Cont.
| | | Enzyme | Substrates | Consequences of polymorphism for drug effects in vivo | Reference | | CYP2E1 | N-Nitrosodimethylamine, acetaminophen, ethanol | Possible effect on alcohol consumption | (10) | | CYP3A4/3A5/3A7 | Macrolides, cyclosporin, tacrolimus, calcium channel blockers, midazolam, terfenadine, lidocaine, dapsone, quinidine, triazolam, etoposide, teniposide, lovastatin, alfentanil, tamoxifen, steroids, benzo(a)pyrene | Not yet elucidated | (11) | | Aldehyde dehydrogenase (ALDH2) | Cyclophosphamide, vinyl chloride | SCE frequency in lymphocytes | (12) | | Alcohol dehydrogenase (ADH3) | Ethanol | Increased alcohol consumption and dependence | (13) | | Dihydropyrimidine dehydrogenase | Fluorouracil | 5-fluorouracil neurotoxicity | (14) | | NQO1 (DT-diaphorase) | Ubiquinones, menadione, mitomycin C | Menadione-associated urolithiasis | (15) |
| Phase II Enzymes | | | |
| N-Acetyltransferase (NAT1) | p-Aminosalicylic acid, p-aminobenzoic acid, sulfamethoxazole | Not yet elucidated | (16) |
| N-Acetyltransferase (NAT2) | Isoniazid, hydralazine, sulfonamides, amonafide, procainamide, dapsone, caffeine | Hypersensitivity to sulfonamides, amonafide toxicity, hydralazine-induced lupus, isoniazid neurotoxicity | (16-18) |
| Glutathione S-transferase (GSTM1) | Aminochrome, dopachrome, adrenochrome and noradrenochrome | Not yet elucidated | (19) |
| Glutathione S-transferase (GSTM3) | | Not yet elucidated | (19) |
| Glutathione S-transferase (GSTT1) | | Not yet elucidated | (19) |
| Glutathione S-transferase (GSTP1) | 13-cis retinoic acid, ethacrynic acid, acrolein, epirubicin | Not yet elucidated | (19, 20) | | Sulfotransferases | Steroids, acetaminophen, estrogens, dopamine, epinephrine, naringenin | Not yet elucidated | (21) | | Catechol-O-methyltransferase | Estrogens, levodopa, ascorbic acid | Substance abuse, levodopa response | (22) | | Histamine methyltransferase | Histamine | Not yet elucidated | (23) | | Thiopurine methyltransferase | Mercaptopurine, thioguanine, azathioprine | Thiopurine toxicity and efficacy, risk of second cancers | (24, 25) | | UDP-glucuronosyl-transferase (UGT1A1) | Irinotecan, bilirubin | Irinotecan glucuronidation | (26) | | UDP-glucuronosyl-transferase (UGT2Bs) | Opioids, androgens, morphine, naproxen, ibuprofen | Not yet elucidated | (27) |
| Transporters | | | |
| BSEP | Conjugates | Not yet elucidated | (28) |
| MDR-1 | Natural product anticancer drugs, CYP3A4 substrates, digoxin | Not yet elucidated | (29, 30) | | MRPs | Glutathione, glucuronide, and sulfate conjugates, nucleoside antivirals | Not yet elucidated | (31) | | |
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| Supplemental Table 2. Genetic polymorphism of drug receptors or targets linked to altered drug effects in humans. |
| Receptor/target | Medication | Drug effects linked to receptor/target polymorphism | Reference | |
| b2-Adrenergic receptor | Albuterol | Response in asthmatics | (32) |
| 5-Lipoxygenase promoter | ABT-761 (zileuton) | Response in asthmatics | (33) |
| Angiotensin-converting enzyme (ACE) | Enalapril, isinopril, captopril | Renoprotective effects, cardiac indices, blood pressure, IgA nephropathy | (34, 35) |
| Cholesteryl ester transfer protein | Pravastatin | Progression of atherosclerosis | (36) |
| Stromelysin | Pravastatin | Efficacy in coronary atherosclerosis and restenosis | (37) |
| Angiotensin-II T receptor | Perindopril nitrendipine | Change in arterial stiffness | (38) |
| Sulfonylurea receptor | Tolbutamide | Serum C-peptide and insulin response | (39) |
| 5-Hydroxytryptamine 2C receptor | Clozapine | Response in schizophrenia | (40) |
| 5-Hydroxytryptamine 2A receptor | Clozapine and other neuroleptics | Response in schizophrenia | (41) |
| Serotonin transporter promoter | Fluvoxamine | Response in delusional depression | (42) |
| Dopamine D2 and D3 receptors | Antipsychotics | Drug-induced tardive dyskinesia | (43) |
| Vitamin D receptor | 1,25-Dihydroxy vitamin D3 | Vitamin D response in rickets | (44) |
Glucocorticoid receptor | Dexamethasone | Cortisol and insulin response | (45) |
| Nicotinic receptor | Acetylcholine (-) nicotine | Increased sensitivity to agonist effects | (46) |
| Delta opioid receptor | Heroin | Addiction | (47) |
| Potassium channels | | | |
| HERG | Quinidine | Drug-induced long QT syndrome | (48) |
| Cisapride | Drug-induced torsade de pointes | |
| KvLQT1 | Terfenadine, disopyramide meflaquine | Drug-induced long QT syndrome | |
| hHCNE2 | Clarithromycin | Drug-induced arrhythmia | (49) |
| Sodium channel | | | |
| SCN5A | Mexiletine | Efficacy for long-QT syndrome secondary to SCN5A mutations but not HERG mutations | (50) |
| Inositol-p1p | Lithium | Response of manic depressive illness | (51) |
| HLA-DRB1 | Cyclosporin A | Response of aplastic anemia | (52) |
| Apolipoprotein E4 | Tacrine | Response of Alzheimer's disease | (53) |
| Ryanodine receptor | Halothane or succinylcholine | Drug-induced malignant hyperthermia | (54) |
| Prothrombin | Oral contraceptives | Risk of cerebral-vein thrombosis | (55) | | | Peroxisome proliferator- activated receptor | Insulin | Insulin sensitivity | (56) |
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