5, 29 Very little information exists on the role of hepatic basolateral drug transporters selleck inhibitor in the development of drug-induced cholestasis although it has been speculated that increased expression of the organic anion transporting peptides (OATPs) and other drug uptake transport proteins might enhance the hepatic concentrations of certain drugs, thus predisposing the subject to cholestatic reactions. Oatp1b2 knockout mice are resistant to the hepatotoxic effects of the mushroom poison phalloidin, consistent with the role of OATPs in increasing the concentration of substrate drugs/toxins.66 Although 14 nonsynonymous SLC1B1 single-nucleotide polymorphisms

that encode OATP1B1 have been described by Tirona et al.67 in African Americans and Europeans, six of these reduce rather than enhance the uptake of the OATP1B1 substrates estrone-3-sulfate and estadiol-17-glucuronide in in vitro studies. Genetic variants in OATP1B1 can influence the hepatic uptake of drugs like pravastatin and irinotecan.

In one reported case, mutations in this transporter resulted in statin-induced myopathy,68 which was explained by a decrease in turnover rate of this transporter.69 More information is known about the functional and clinical impact of genetic variations in the canalicular transporters and their role in drug-induced cholestasis. One study using 110 healthy liver tissues demonstrated considerable variation in the expression of these proteins with 32% expressing low levels of at least one of the canalicular HSP90 transport click here proteins, a feature that could predispose individuals to cholestatic drug injury.70 Several common polymorphisms for canalicular ABC transporters have

also been identified in healthy individuals by systematic genetic screening of their promoter and coding regions.71-73 Polymorphisms such as C1515Y in MRP2, V444A in BSEP, and C3435T in MDR1 were found to be associated with decreased hepatic expression of these proteins.70, 74 These polymorphisms can influence the bioavailability of drugs. For example, the C3435T polymorphism in MDR1 increases oral bioavailability of digoxin, but has no effect on the bioavailability of cyclosporine A.74, 75 However, considerable interindividual variability exists in the expression of the canalicular membrane ABC transporter proteins with 15%-20% of individuals being classified as low or very low expressers of at least one of these proteins in one study.70 Differences in genetic variability of MDR3 and BSEP and haplotype structures in different healthy individuals may predispose different ethnic populations to drug-induced cholestasis.76 Two nonsynonymous single-nucleotide polymorphisms in BSEP have been described for c.1331TC (p.V444A) in exon 13 and c.2029AG (p.M677V) in exon 17 with frequencies that are higher than 0.5% in different cohorts.70 In another study, individuals with the p.