Annotated PGx Gene Information for CYP3A4
Submitted by: Alan Shuldiner (PAPI), Michelle Whirl Carillo, Joan M. Hebert (PharmGKB)
Reviewed by: Under Review
Submitted date: July, 2007
| Gene HGNC Name: | CYP3A4 |
|---|---|
| Introductory Information: |
CYP3A4 (cytochrome P450 3A4) encodes a member of the cytochrome P450 superfamily of enzymes. CYP3A4 and CYP3A5 are believed to be the predominant cytochrome P450s expressed in adult human liver, with CYP3A4 thought to dominate in Whites and CYP3A5 in Blacks /African Americans. The two have overlapping substrate specificities. CYP3A4 is responsible for the metabolism of approximately 50-60% of clinical drugs used today, including acetaminophen, codeine, cyclosporine A, diazepam, and erythromycin. It is important for the metabolism of steroid hormones [PMID: 9667077, 9054608, 9187528, 3259858]. The complete cDNA sequence was reported by Molowa et al. in 1986 [PMID: 3460094] and Inoue et al. later mapped the gene to 7q22.1 by fluorescence in situ hybridization [PMID: 1391968]. The gene is about 27 kb in length and contains 13 exons and 12 introns [PMID: 8269949]. Linkage results from a Japanese population[PMID: 14695543] demonstrate that CYP3A4 and CYP3A5 haplotypes are closely linked and that the two genes are in the same gene block, so some effects originally thought to be due to a CYP3A4 allele are probably actually due to a CYP3A5 allele in linkage disequilibrium. Though extensively studied, most of the CYP3A4 haplotypes have not been indisputably shown to affect expression or activity in terms of pharmacodynamics or pharmacokinetics. One recently discovered rare haplotype, CYP3A4*20, contains a premature stop codon which does result in a truncated protein and complete loss of function [PMID: 16580902; this publication also contains excellent overview information for CYP3A4.]. This haplotype has been identified in only one family(of Brazilian origin) to date. The g.82,266 (on AF280107 ) polymorphism(part of haplotypes *18B and *19) may contribute to variability in response to clopidogrel (which requires metabolism by CYP3A4 to be active). This study was done in a Spanish (White) population of coronary artery disease patients also being treated with aspirin [PMID: 16645157]. The *16B haplotype has been reported to result in altered paclitaxel metabolite levels in Japanese(Asian) cancer patients [PMID: 16890579]. One study showed that cancer patients carrying CYP3A4*1B may have a higher rate of docetaxel clearance and so a lower exposure to docetaxel [PMID:16765145], though this actually may be due to the linked CYP3A5*1. However, Lewis et al. [PMID: 17545536 ] found no significant relationship between CYP3A4*1B and docetaxol clearance in African American (Black or African American) and Caucasian(White) cancer patients. Chu et al. recently found that white female breast cancer patients who are CYP3A4 *1B carriers may have an increased risk of developing endometrial cancer after tamoxifen treatment when compared with non-*1B carriers [PMID: 17434921]. In vitro, CYP3A*1B has been reported to lead to increased transcription [PMID: 14673875], though there have been conflicting results as well [PMID:14515058]. Also see Lamba et al. [PMID: 12406645], Lee and Goldstein [PMID: 16004554] and http://www.imm.ki.se/cypalleles/cyp3a4.htm . |
| Key PubMed IDs: | 3460094, 1391968,14695543, 16580902, 10668853 ,16645157,16890579,16765145,14515058 ,17545536 , 9667077, 9054608, 9187528, 3259858 ,8269949, 17434921 , 14673875,12406645,16004554 |
| Key Pathways: |
Cyclophospamide Pathway(PK) Etoposide Pathway Ifosfamide Pathway(PK) Irinotecan Pathway Antiestrogen Pathway (Tamoxifen PK) Doxorubicin Pathway (PK) Phenytoin Pathway(PK) Statin Pathway(Atorvastatin, Lovastatin and Simvastatin PK) Statin Pathway(Fluvastatin PK) Statin Pathway(PK) Warfarin Pathway(PK) |
| Drugs/Substrates: | CYP3A4 is involved in the metabolism of 50-60% of clinically used drugs. From http://medicine.iupui.edu/flockhart/htm : Macrolide antibiotics: clarithromycin, erythromycin, telithromycin; Anti-arrhythmics: quinidine=>3-OH Benzodiazepines: alprazolam, diazepam=>3OH, midazolam, triazolam; Immune Modulators: cyclosporine, tacrolimus (FK506); HIV Antivirals: indinavir, nelfinavir, ritonavir, saquinavir; Prokinetic: cisapride; Antihistamines: astemizole, chlorpheniramine, terfenidine; Calcium Channel Blockers: amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil; HMG CoA Reductase Inhibitors: atorvastatin, cerivastatin, lovastatin, simvastatin; Steroid 6beta-OH: estradiol, hydrocortisone, progesterone, testosterone; Miscellaneous drugs: alfentanil, aprepitant, aripiprazole, buspirone, cafergot, caffeine=>TMU, cilostazol, cocaine, codeine- N-demethylation, 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 |
| Phenotypes/Diseases: | Diseases: Chronic Hepatitis C - hypothesized association found to be non-significant [PMID: 12087352]; treatment-related leukemia: association found [PMID: 9789061] vs. no association found [PMID: 12439220] ; prostate cancer : association found [PMID:9719084 , 10548319] vs. no association [PMID: 12107441]. Small Cell Lung Cancer [PMID: 14515059]-association found in women. Endometrial Cancer after Tamoxifen treatment: potential association found [PMID: 17434921]. See Curated Phenotype Datasets |
| Important Variants: | CYP3A4:-392A>G, CYP3A4:M445T, CYP3A4: D174H, CYP3A4: P416L, CYP3A4:L15P, CYP3A4:R162Q, CYP3A4:T185S, CYP3A4:F189S, CYP3A4: P467S |
| Important Haplotypes: |
CYP3A4*1A, CYP3A4*1B, CYP3A4*1C, CYP3A4*1D, CYP3A4*1E, CYP3A4*1F, CYP3A4*1G, CYP3A4*1H, CYP3A4*1J, CYP3A4*1K, CYP3A4*1L, CYP3A4*1M, CYP3A4*1N, CYP3A4*1P, CYP3A4*1Q, CYP3A4*1R, CYP3A4*1S, CYP3A4*1T, CYP3A4*2, CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*7, CYP3A4*8, CYP3A4*9, CYP3A4*10, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*14, CYP3A4*15A, CYP3A4*15B, CYP3A4*16A, CYP3A4*16B, CYP3A4*17, CYP3A4*18A, CYP3A4*18B, CYP3A4*19,CYP3A4*20 |