The farnesoid X receptor (FXR) is an important nuclear receptor involved in the regulation of bile acid transport and homeostasis. Variants in the FXR gene NR1H4 have been associated with ICP and cholesterol cholelithiasis.102, 103 The FXR*1B haplotype (containing a −1GT substitution in the nucleotide adjacent to the translation initiation site) leads to reduced FXR activity compared with FXR*1A (−1G), and this has been associated with reduced expression of the FXR target genes SLCO1B3 and short heterodimer partner SHP in a human

liver bank.104 It is conceivable that the genetic variants that predispose to ICP (e.g., −1GT and Met173Thr)102 could also play a role in cholestatic liver injury caused by drugs such Doramapimod as oral contraceptives. However, this association analysis remains to be performed. New mechanistic concepts of DILI have defined new targets for pharmacogenetic association studies. Recent studies have subsequently been able to identify drug-specific as well as nonspecific genetic risk factors for DILI and, in turn, refined our knowledge of hepatotoxic mechanisms. Their results suggest that for many drugs, the genetic variability of the HLA system is the single most important risk factor for DILI, and that variability of factors relating

to oxidative stress and other mechanisms also play an important role. In contrast, polymorphisms of drug-metabolizing enzymes have some effect, but they appear to play a lesser role than previously assumed. New insights into the mechanisms BYL719 cost of DILI see more have opened the path to the development of new treatments such as enzyme inhibitors, antioxidant agents, or modifiers of immune reactions and inflammatory processes such as anti–TNF-alpha agents.

On the other hand, the increasing number of identified low-risk factors with their complex and still poorly understood interactions also explain why we are still not able to predict idiosyncratic DILI in individual patients with clinically relevant precision; this situation is unlikely to change for most hepatotoxic drugs in the near future. Until then, immediate cessation of treatment with a drug that is suspected to cause severe DILI in an individual patient remains the most important measure in clinical practice. From a regulatory perspective, pharmacogenetics of DILI has important implications. The cases of ximelagatran hepatotoxicity14 and simvastatin myopathy93 demonstrated that GWAS can successfully identify genetic risk factors for adverse drug reactions in data from large phase 3 clinical trials. The so-called rezulin rule states that mild to moderate increases of aminotransferases in clinical trials are quantitatively related to the less frequent occurrence of more severe DILI in the postmarketing phase.