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Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis


Stieger, B; Geier, A (2011). Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis. Expert Opinion on Drug Metabolism & Toxicology, 7(4):411-425.

Abstract

INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION: Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.

INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION: Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:23 Aug 2011 14:13
Last Modified:05 Apr 2016 14:59
Publisher:Informa Healthcare
ISSN:1742-5255
Publisher DOI:10.1517/17425255.2011.557067
PubMed ID:21320040
Permanent URL: http://doi.org/10.5167/uzh-49200

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