Annotated PGx Gene Information for ABCB1
Submitted by: Jason Gow, Leslie Chinn (PMT)
Reviewed by: Reviewed
Submitted date: August 11, 2006
| Gene HGNC Name: | ABCB1 |
|---|---|
| Gene Common Name: | MDR1 |
| Introductory Information: | The ABCB1 gene is a member of the ATP-binding cassette (ABC) transporter superfamily. The gene is also known as the multidrug-resistance 1 (MDR1) gene and its protein product is called P-glycoprotein (P-gp). ABCB1 is expressed in barrier and excretory tissues that have protective or elimination roles, such as the intestines, liver, kidney, blood-brain barrier, and placenta. ABCB1 over-expression in tumors has been implicated in multidrug resistance to cancer chemotherapeutic agents. Located on the plasma membrane, P-gp can transport a wide range of endogenous and exogenous compounds out of the cell [PMID: 10331089]. Substrates of P-gp include anticancer agents, cardiac drugs and HIV protease inhibitors. Studies have demonstrated the existence of interindividual variability in P-gp expression and function as well as clinical phenotypes related to P-gp [PMID: 7473127]. ABCB1 is located on chromosome 7q21.1 and was originally cloned by Riordan et al. in 1985 [PMID: 2863759]. The gene consists of 29 exons spanning nearly 200 kb of genomic DNA; however only 27 exons code for P-gp. There are multiple transcriptional start sites but the primary start site produces an mRNA transcript of 4360 bp that contains 28 exons. Currently, there is no evidence for the existence of splice variants. P-glycoprotein has 1280 amino acids, 12 transmembrane domains and two ATP-binding domains [PMID: 10331089]. ABCB1 has approximately 116 polymorphic sites in Caucasians and 127 in African Americans with a minor allele frequency greater than 5% (www.hapmap.org [PMID: 12893986, 11503014, 10716719]). Some of the most commonly studied variants are 1236C>T, 2677G>A/T and 3435C>T and the most commonly studied haplotype involves the 1236, 2677 and 3435 SNPs. There are many other ABCB1 variants such as -129C>T (5'-UTR), 61A>G (Asn21Asp) and 1199G>A (Ser400Asn) that have been studied in vivo and in vitro. To date, there is no clear consensus on the impact of any of these variants on drug disposition, response or toxicity. For the most commonly studied phenotypes, i.e. intestinal absorption and CNS penetration, discordant results have been published and appropriately powered studies are still needed to clarify these results. Helpful review papers have been written that summarize the substantial body of work covering ABCB1 polymorphisms and their potential impact on cellular and clinical phenotypes [PMID: 12505329, 12406646, 14749689, 15212152]. |
| Key PubMed IDs: | 12505329, 12406646, 14749689, 15212152, 10331089, 2863759, 7473127, 11503014, 12893986, 10716719 |
| Key Pathways: | Etoposide, Irinotecan |
| Drugs/Substrates: | Doxorubicin, Daunorubicin, Etoposide, Irinotecan, Paclitaxel, Topotecan, Vinblastine, Talinolol, Digoxin, Verapamil, Atorvastatin, Fexofenadine, Ritonavir, Cyclosporine, Tacrolimus, Amitriptyline, Loperamide, Rhodamine 123, Indinavir, Saquinavir [PMID: 14749689, 10331089] |
| Phenotypes/Diseases: | |
| Important Variants: | ABCB1:1236C>T , ABCB1:2677G>A/T, ABCB1:3435C>T |
| Important Haplotypes: | 1236 C>T, 2677 G>T, 3435 C>T named *1 (CGC) or *2 (TTT) [PMID: 11503014, Kim et al. 2001]; 1236, 2677, 3435 (TTT) and 3 intronic SNPs (intron 9, intron 13, intron 14) named ABCB1:*13 [PMID: 12893986, Kroetz et al. 2003] |