Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump

Abstract

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound-and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energydependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILIconcern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs. Conclusion: These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI. (HEPATOLOGY 2014;60:1015-1022

Mitochondrial toxicity assessment in industry – a decade of technology development and insight

“…However, it must be noted, the Porceddu et al study [25] did not take into account other possible mechanisms that could contribute to liver injury such as reactive metabolite formation, ROS formation, glutathione depletion, BSEP inhibition and other plasma membrane transporters, as mentioned above. Recently, Aleo et al [26] have shown that there is a very strong correlation with severe liver injury, when both BSEP and mitochondrial function are inhibited, compared to when only one is impaired.…”

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“…9 Therefore, drug-induced and/or bile acid-induced dual inhibition of mitochondrial and BSEP functions might result in prolonged and severe drug-induced cholestasis, as in the case presented here. 10 Although rapid reversal of liver cholestasis after cessation of the insulting drug is expected in the simple form of drugrelated BSEP malfunction, severe and prolonged cholestasis requiring medical intervention (as presented in our case) can be theoretically explained by this dual-inhibition mechanism.…”

Bile acids in drug induced liver injury: Key players and surrogate markers

“…Aleo et al, for example, assessed various compounds with Most-DILI-, Less-DILI-and No-DILI-concern and found that drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI and more restrictive product safety labeling related to liver injury [87]. In the case of TGZ, reactive metabolite formation and mitochondrial dysfunction are considered to be critical steps in DILI pathogenesis in addition to inhibition of BSEP [73,74,88].…”