Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus, M.D.; Peter J. Meier, M.D.; Bruno Stieger, Ph.D.

Disclosures

Semin Liver Dis. 2010;30(2):147-159. 

In This Article

Genetics of Drug-induced Cholestasis

Investigations of the genetics of DILI have proved taxing, both because of their low incidence and their difficulty in replicating observed associations. Nevertheless, progress has now been achieved by both candidate-gene and genome-wide association approaches. In particular, associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury, and the HLA class I B*5701 allele are now established.[148,149] Although associations are so far drug-specific, more general susceptibility genes for DILI may exist. However, elucidation of these links requires further investigation, ideally by using large cohorts involving international collaboration.

Therefore, the functional and clinical impact of genetic variations in ABCB11 and ABCB4 for the development of DILI and, more specifically, cholestasis, is currently under investigation.[150] A Swiss study in 36 patients with drug-induced cholestasis supports a role of ABCB11 and ABCB4 mutations and polymorphisms in this condition. Specifically, full-length sequencing of ABCB11 and ABCB4 revealed a heterozygous p.D676Y mutation in BSEP observed in a patient taking fluvastatin and a heterozygous p.I764L mutation in MDR3 observed in a patient taking risperidone:[115] both suffered from hepatocellular cholestasis. The pathogenic implications of these mutations remain, however, unclear. In the case of BSEP, in vitro taurocholate transport was unchanged for the mutated protein whereas the impact of the p.I764L mutation on MDR3 expression and function was not investigated. In the same study, the BSEP p.V444A polymorphism was observed significantly more frequent in patients with drug-induced cholestasis than in patients with drug-induced hepatocellular injury and healthy controls, with the AA phenotype being encountered in 61% of cholestatic patients compared with 31% and 32% in patients with hepatocellular injury and healthy controls, respectively. Overall, carriers of the alanine phenotype carried a threefold increased risk to develop a cholestatic drug side effect under treatment with different drugs, such as β-lactam antibacterials, psychotropic drugs, and proton-pump inhibitors. However, the underlying mechanism remains still unclear, as none of these drugs could be shown to inhibit BSEP function in vitro (unpublished results). It can be speculated whether BSEP-inhibiting drugs with known cholestatic potential, such as cyclosporine, rifampicin, rifamycin, glibenclamide, troglitazone, or bosentan,[37,44,45,145] might predispose to the development of cholestasis in carriers of the alanine allele.

Only limited information is available so far on the functional consequences of genetic variation in basolateral transporter systems. Tirona et al identified 14 nonsynonymous SLCO1B1 polymorphisms SNPs in a population of African Americans and European Americans,[151] six of which exhibited reduced in vitro uptake of the OATP1B1 substrates estrone-3-sulfate and estradiol-17β-glucuronide. SLCO1B1 genetic variants have also been associated with interindividual differences in hepatic disposition of pravastatin and irinotecan, respectively.[152–155] Furthermore, the cellular uptake of the lipid-lowering drug rosuvastatin is highly dependent on NTCP and OATP function and varies upon the underlying SLCO1A1 and SLCO haplotypes.[156] Although the impact of these observations for the development of cholestasis remains to be studied, it could be speculated that differences in NTCP and OATP mediated basolateral drug uptake predisposes to the development of cholestasis by determining intracellular drug levels and hence, the concentration of potential competitive inhibitors of apical efflux transporters.

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