Table 1.
Overview of Common Genetic Variants in Phase I Drug Metabolising Enzymes
| Gene | Important Variants | Variation | Consequence of Variation | Effect on Enzyme Activity | Selected Medication Substrates |
|---|---|---|---|---|---|
| CYP2D6 | CYP2D6*3 | 2549 del A (rs4986774) | Frameshift mutation, premature stop | Absent activity | Amitriptyline, atomoxetine, carvedilol, chlorpheniramine, chlorpromazine, citalopram, clomipramine, clozapine, codeine, debrisoquine, desipramine, dextromethorphan, doxepin, flecainide, fluoxetine, fluvoxamine, gefitinib, haloperidol, imipramine, maprotiline, metoprolol, mexilet-ine, mianserin, morphine, nortriptyline, paroxetine, risperidone, tamoxifen, thioridazine, timolol, tolterodine, tramadol |
| CYP2D6*4 | 1846G>A (rs3892097) | Splicing defect | Absent activity | ||
| CYP2D6*5 | n/a | Whole gene deletion | Absent activity | ||
| CYP2D6*6 | 1707 del T (rs5030655) | Frameshift mutation | Absent activity | ||
| CYP2D6*9 | 2615_2617delAAG (rs5030656) | Deletion of lys281 | Reduced activity | ||
| CYP2D6*10 | 100C>T (rs1065852) | pro34ser | Reduced activity | ||
| CYP2D6*17 | 1023C>T (rs28371706) | thr107ile | Reduced activity* | ||
| CYP2D6*29 | 3183G>A (rs59421388) and 4180G>C (rs61736512) | val338met and ser486thr | Reduced activity | ||
| CYP2D6*41 | 2988G>A (rs28371725) | Splicing defect | Reduced activity | ||
| CYP2D6*UM | n/a | Additional functional copies (2-13) of gene | Increased activity | ||
| CYP2C19 | CYP2C19*2 | 681G>A (rs4244285) | Splicing defect, premature stop | Absent activity | lansoprazole, omeprazole, pantoprazole, rabeprazole, phenytoin, phenobarbitone, amitriptyline, carisoprodol, clopidogrel, citalopram, clomipramine, cyclophos-phamide, hexobarbital, imipramine, indomethacin, nelfi-navir, nilutamide, primidone, progesterone, proguanil, propranolol, teniposide, warfarin |
| CYP2C19*3 | 636G>A (rs4986893) | Premature stop | Absent activity | ||
| CYP2C9 | CYP2C9*2 | 430C>T (rs1799853) | arg144cys | Reduced activity | irbesartan, losartan, phenytoin, cyclophosphamide, tamoxifen, fluvastatin, celecoxib, diclofenac, ibuprofen, meloxicam, naproxen, glibenclamide, glimepiride, glipizide, tolbutamide, warfarin |
| CYP2C9*3 | 1075A>C (rs1057910) | ile359leu | Reduced activity | ||
| CYP3A4 | No clinically relevant variants described to date | N/A | N/A | N/A | clarithromycin, erythromycin, telithromycin, quinidine, alprazolam, diazepam, midazolam, triazolam, cyclosporine, tacrolimus, indinavir, nelfinavir, ritonavir, saquinavir, cisapride, astemizole, chlorpheniramine, terfenidine, amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, estradiol, hydrocortisone, progesterone, testosterone, alfentanil, aprepitant, aripiprazole, buspirone, cafergot, caffeine, cilostazol, cocaine, codeine, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM, lidocaine, methadone, nateglinide, ondansetron, pimozide, propranolol, quetiapine, quinine, risperidone, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, ziprasidone, zolpidem |
| CYP3A5 | CYP3A5*3 | 6986A>G (rs776746) | Splicing defect, premature stop | Absent activity | Broad overlap with CYP3A4 |
| CYP3A5*6 | 14690G>A (rs10264272) | Splicing defect, removes exon 7 | Absent activity | ||
| CYP3A5*7 | 27131-2insT (rs41303343) | Frameshift mutation | Absent activity | ||
| CYP2B6 | CYP2B6*6 | 516G>T (rs3745274) | his172gln | Reduced activity | bupropion, cyclophosphamide, diazepam, efavirenz, ifosfamide, ketamine, methadone, MDMA, meperidine, mephenytoin, midazolam, nevirapine, nicotine, propofol, selegiline, tamoxifen |
| CYP2B6*I6 | 983T>C (rs28399499) | ile328thr | Reduced activity | ||
| CYP2B6*I8 | 1459C>T (rs3211371) | arg487cys | Reduced activity |
Data compiled from http://www.pharmgkb.org and http://www.cypalleles.ki.se. Bold type indicates drug of particular interest to the corresponding gene.
*
while CYP2D6*I7 is generally considered to be a reduced function allele, evidence exists that this variant has normal activity towards risperidone [146].