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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35097

Russmann, S; Jetter, A; Kullak-Ublick, G A (2010). Pharmacogenetics of drug-induced liver injury. Hepatology, 52(2):748-761.

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Abstract

Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI. (HEPATOLOGY 2010).

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > Center for Integrative Human Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:19 Jul 2010 12:03
Last Modified:27 Nov 2013 16:19
Publisher:Wiley-Blackwell
ISSN:0270-9139
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1002/hep.23720
PubMed ID:20607838
Citations:Web of Science®. Times Cited: 44
Google Scholar™
Scopus®. Citation Count: 56

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