Pharmacogenomics of human OATP transporters

Abstract

Organic anion transporting polypeptides (OATPs) mediate the uptake of a broad range of compounds into cells. Substrates for members of the OATP family include bile salts, hormones, and steroid conjugates as well as drugs like the HMG-CoA-reductase inhibitors (statins), cardiac glycosides, anticancer agents like methotrexate, and antibiotics like rifampicin. OATPs are expressed in a variety of different tissues, including intestine, liver, kidney, and brain, suggesting that they play a critical role in drug absorption, distribution, and excretion. The identification and functional characterisation of naturally occurring variations in genes encoding human OATP (SLCO) family members is in the focus of transporter research. As a result of their broad substrate spectrum and their wide tissue distribution, altered transport characteristics or protein localisation can contribute significantly to interindividual variations of drug effects. The analysis of the consequences of genetic variations in genes encoding transport proteins may, therefore, contribute to a better understanding of interindividual differences in drug effects and to individualise treatment regimens with drugs that are substrates for human OATP proteins. In this review, we summarise the current knowledge on genetic variations in transporter genes encoding human OATP family members and their functional consequences analysed by in vitro and in vivo studies.

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

“…This might have sweeping consequences for drug pharmacokinetics in patients, since many SNPs have been identified in the SLCO1B1, SLCO1B3, and SLCO1A2 genes, some of which are responsible for markedly reduced transport capacities (reviewed in ref. 6). For example, individuals carrying SLCO1B1*15 (388A>G and 521T>C) have markedly increased plasma levels of statins and are at increased risk of developing statin-induced myopathy (6,7).…”

“…6). For example, individuals carrying SLCO1B1*15 (388A>G and 521T>C) have markedly increased plasma levels of statins and are at increased risk of developing statin-induced myopathy (6,7). SLCO1B1*15 has also been associated with life-threatening toxicities in patients treated with irinotecan (8).…”

“…OATP1A/1Bs therefore also present a significant factor in drug-drug interactions. Additionally, various SNPs have been identified in human SLCO1A/1B genes, especially in SLCO1B1, some of which have been associated with increased plasma levels of statins and irinotecan in patients, sometimes resulting in severe and life-threatening toxicity (6)(7)(8). Genetic variation in SLCO1A/1B genes, resulting in altered transport activity, might therefore be an important factor in interindividual variation in response to drug treatment.…”

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

“…The hepatic clearance of numerous organic anions, including drugs and xenobiotics, is mainly facilitated by the Na + -independent uptake by organic anion transporting polypeptides (OATPs) (8,9) and organic anion transporters (OATs) (10). In human hepatocytes, OATP1B1, OATP1B3, and OATP2B1 isoforms are expressed at the basolateral plasma membrane of hepatocytes.…”

Topological aspects of oligomeric UDP-glucuronosyltransferases in endoplasmic reticulum membranes: Advances and open questions

“…The intraluminal orientation of the active site of UGTs and of β-glucuronidase in ER membranes necessitates a number of transporters in these membranes. Following transport of glucuronides between ER lumen and cytosol, conjugate transporters in the plasma membrane are required to prevent the accumulation of polar conjugates in cells [6][7][8]. Recently, accumulating evidence suggests that UGTs are functional in …”