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Novel insights into bile acid detoxification via CYP, UGT and SULT enzymes

Kastrinou Lampou, Vlasia, Poller, Birk, Huth, Felix, Schadt, Heiko, Fischer, Audrey, Kullak-Ublick, Gerd-Achim, Camenisch, Gian P. and Michael, Arand (2022) Novel insights into bile acid detoxification via CYP, UGT and SULT enzymes. Toxicology in vitro.


Bile acid (BA) homeostasis is a complex and precisely regulated process to prevent impaired BA flow and the development of cholestasis. Several reactions, namely hydroxylation, glucuronidation and sulfation are involved in BA detoxification. In the present study, we employed a comprehensive and quantitative approach using human recombinant enzymes, human liver microsomes (HLM) and human liver cytosol (HLC) to delineate the interplay of the enzymatic processes involved in hepatic BA metabolism. We showed that CYP3A4 was a crucial step for the metabolism of several BA and their taurine and glycine conjugated forms and quantitatively described their metabolites. Glucuronidation and sulfation were also identified as important drivers of the BA detoxification process in humans. Moreover, lithocholic acid (LCA), the most hydrophobic BA with the highest toxicity potential, was a substrate for all investigated processes, demonstrating the importance of hepatic metabolism for its clearance. Collectively, this study describes the major contributing (metabolic) processes in the BA detoxification network and suggests that the inhibition potential of candidate drugs on CYP3A4, UGT1A3, UGT2B7 and SULT2A1 need to be assessed, together with inhibition of the relevant hepatic transporters and potential toxic metabolite formation, in the preclinical investigations of drug-induced cholestasis in humans.

Item Type: Article
Date Deposited: 20 Dec 2022 00:45
Last Modified: 20 Dec 2022 00:45


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