Annotated PGx Gene Information for CYP3A5
Submitted by: Jatinder Lamba, Erin Schuetz (PAAR)
Reviewed by: Reviewed
Submitted date: February 16, 2006
| Gene HGNC Name: | CYP3A5 |
|---|---|
| Gene Common Name: | CYP3A5 |
| Introductory Information: | The human CYP3A subfamily, CYP3A4, CYP3A5, CYP3A7 and CYP3A43, is one of the most versatile of the biotransformation systems that facilitate the elimination of drugs. CYP3A4 and CYP3A5 together account for approximately 30% of hepatic cytochrome P450 and approximately half of medications that are oxidatively metabolized by P450 are CYP3A substrates. Although both CYP3A4 and CYP3A5 are expressed in liver and intestine, CYP3A5 is the predominant form expressed in extrahepatic tissues. The CYP3A5 cDNA sequence was first described independently by Aoyama et al. [PMID: 2732228] and Schuetz et al. [PMID: 2802615]. The CYP3A5 gene is localized on Chromosome 7q22.1 along with other CYP3A family members. The gene consists of nine exons and encodes a 502 amino acid protein. CYP3A5 expression is polymorphic [PMID: 11279519]. On the CYP allele nomenclature web site, 25 allelic variants of CYP3A5 have been reported by various investigators. Functional CYP3A5 is encoded by the CYP3A5*1 allele. The most common nonfunctional variant of CYP3A5 is a G>A change at position 22893 (AC005020) and is encoded by CYP3A5*3 [PMID: 11279519] (on the CYP allele nomenclature web site mentioned above CYP3A5*3 is designated as 6986A>G). CYP3A5*6 (14690G>A) is a less common nonfunctional allele present predominantly in the African American population, but occasionally found in other populations [PMID: 11279519]. CYP3A5*7 has a 27131-2ins T (number from CYP allele webpage) insertion and occurs with a frequency of 10% in the African American population [PMID: 11740341]. Liver microsomes from individuals homozygous for the nonfunctional CYP3A5*3 genotype have about half the overall CYP3A catalytic activity toward midazolam, which is a substrate for CYP3A5 and CYP3A4, compared with individuals with at least one wild-type CYP3A5*1 allele [PMID: 11279519]. Recent reports have demonstrated an association of CYP3A5 genotype with hypertension [PMID: 15492926, 12694072, 12754175, 15952872] and with the in vivo disposition of clinically important drugs such as tacrolimus [PMID: 15814280, 15729180, 15723604, 15808586], saquinavir clearance and Cmax [PMID: 15373940, 16338276], dose dependent effects on ABT-773 plasma levels [PMID: 15179406], the lipid lowering effects of statin drugs [PMID: 15900215, 15284534], and midazolam pharmacokinetics in cancer patients [PMID: 16243813]. CYP3A5 genotype also affects the extent of CYP3A drug interactions, both the magnitude of CYP3A induction by rifampin [PMID: 14515058] and the extent of CYP3A inhibition mediated by itraconazole [PMID: 15289787]. |
| Key PubMed IDs: | 2732228, 2802615, 11279591, 15373940, 12065767, 12694072, 15814280, 15492926 |
| Key Pathways: | Irinotecan, Etoposide, Cyclophosphamide and Ifosfamide Pathways |
| Drugs/Substrates: | ( Adapted from http://medicine.iupui.edu/flockhart/table.htm ) Macrolide antibiotics: clarithromycin, telithromycin; 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, 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, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, zolpidem |
| Phenotypes/Diseases: | CYP3A5 genotype is associated with risk of elevated blood pressure and hypertension [ PMID: 12754175, 15952872, 15596575 ]. |
| Important Variants: | CYP3A5*3 , CYP3A5*6 , CYP3A5*7 |