Conclusions
From the examples provided in this article it is apparent that the genetically determined dysfunction of hepatocellular uptake and excretion of bile salts is an important pathogenic factor for the development of cholestasis. Although the genetic components of ICP and estrogen-induced cholestasis have clearly been established over the last decade, the role of genetics in drug-induced cholestasis is less evident. The heterogeneous and multifactorial nature of drug-induced liver disease makes it not only challenging to clearly link liver disease to a specific drug, but so far impossible to prove the pathogenic role of a specific genetic transporter variant. Future challenges will consist in integrating different genetic determinants of drug toxicity with different environmental and comorbidity-related factors and in a comprehensive system, allowing the cautious use of problematic drugs in susceptible patients.
Disclosure
Bruno Stieger is supported by grant #31003A-124652 from the Swiss National Science Foundation. Christiane Pauli-Magnus is supported by grant #320000-116015 from the Swiss National Science Foundation and a grant from "Forschungsfonds" of the University Basel.
Abbreviations
ABC, ATP-binding cassette; BSEP, bile salt export pump (ABCB11/Abcb11, human/rodent); DILI, drug-induced liver injury; FXR, farnesoid X receptor; GGT, gamma-glutamyl transpeptidase; HLA, human leukocyte antigen; ICP, intrahepatic cholestasis of pregnancy; MDR3, multidrug resistance protein 3 (ABCB4/Abcb4); MRP2, multidrug resistance associated protein 2 (ABCC2/Abcc2); MRP3, multidrug resistance associated protein 3 (ABCC3/Abcc3); MRP4, multidrug resistance associated protein 4 (ABCC4/Abcc4); NTCP, Na+taurocholate cotransporting polypeptide (SLC10A1/SLC10A1); OATP, organic anion transporting polypeptide (SLCO/Slco); OATP1B1, organic anion transporting polypeptide (SLCO1B1/Slco1B1); OATP1B3, organic anion transporting polypeptide (SLCO1B3/Slco1B3); OATP2B1, organic anion transporting polypeptide (SLCO2B1/Slco2B1); SNP, single nucleotide polymorphism; TR−, Mrp2 deficient
Semin Liver Dis. 2010;30(2):147-159. © 2010 Thieme Medical Publishers
Cite this: Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy - Medscape - May 01, 2010.
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