80 In theory, an ABCB11 variant that leads to diminished transport capacity or reduced protein expression of BSEP renders the carrier of this variant more susceptible to inhibition by a drug, because baseline BSEP function is already much lower than normal. A common BSEP variant is located at amino acid position 444, with valine present in 45%-46% (20%-27% in a Japanese population) and alanine in 54%-55% of individuals Doxorubicin manufacturer (1331TC polymorphism in exon 13 of the ABCB11 gene, V444A, rs2287622).81-83 The A444 variant (C allele), although more frequent in the

population, is a susceptibility factor for the development of estrogen-induced cholestasis: in 42 patients with intrahepatic cholestasis of pregnancy (ICP), the C allele was present in 76.2% of cases, compared to 51.3% of controls.84 In four of four patients with contraceptive-induced cholestasis, homozygosity for the

C allele was found. When stratifying a group of 36 Caucasian patients with DILI into 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury, the A444 variant was present in 76% versus 50% of cases, respectively (P < 0.05), compared to 59% allele frequency in healthy controls.85 The odds ratios of having the C allele (A444) were 4.0 (1.3-11.9) when comparing cholestatic DILI with healthy http://www.selleckchem.com/products/GDC-0449.html controls, and 3.2 (1.1-8.9) when comparing cholestatic with hepatocellular DILI. Among the numerous additional ABCB11 mutants described to date, only Asp676Tyr (fluvastatin-induced cholestasis) and Gly855Arg (ethinylestradiol/gestagen-induced cholestasis) have been associated specifically with DILI.85 Although genetic ABCB11 mutants are attributed to cholestatic forms of DILI, data from the Spanish DILI network suggest that BSEP polymorphisms are also associated

with hepatocellular forms Nintedanib (BIBF 1120) of DILI.86 Two other ABC transporters located at the canalicular hepatocyte membrane have been characterized genetically in the context of DILI: the multidrug resistance gene product MDR3 (ABCB4) and the multidrug resistance protein MRP2 (ABCC2). MDR3 is the phospholipid flippase that translocates phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane lipid bilayer. A few ABCB4 mutations have been found specifically in patients with DILI. A heterozygous Ile764Leu mutation in the transmembrane domain of MDR3 (2290AC, exon 18) was observed in a patient with cholestatic DILI taking risperidone, and a Leu1082Gln mutation close to the second ATP binding site (3245TA, exon 25) was observed in a patient with hepatocellular DILI taking amoxicillin-clavulanic acid.85 The multidrug resistance protein MRP2 is an efflux pump for anionic conjugates such as bilirubin diglucuronide, glutathione conjugates, and drug metabolites. In a Korean population, a haplotype containing the g.