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

Kastrinou Lampou, Vlasia; Poller, Birk; Huth, Felix; Fischer, Audrey; Kullak-Ublick, Gerd A; Arand, Michael; Schadt, Heiko S; Camenisch, Gian (2023). Novel insights into bile acid detoxification via CYP, UGT and SULT enzymes. Toxicology in Vitro, 87:105533.

Abstract

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 approach to identify the key enzymes involved in BA metabolism using human recombinant enzymes, human liver microsomes (HLM) and human liver cytosol (HLC). We showed that CYP3A4 was a crucial step for the metabolism of several BAs 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 identified CYP3A4, UGT1A3, UGT2B7 and SULT2A1 as the major contributing (metabolic) processes in the BA detoxification network. Inhibition of these enzymes by drug candidates is therefore considered as a critical mechanism in the manifestation of drug-induced cholestasis in humans and should be addressed during the pre-clinical development.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology

04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Toxicology
Uncontrolled Keywords:Toxicology, General Medicine
Language:English
Date:1 March 2023
Deposited On:28 Feb 2023 16:29
Last Modified:29 Oct 2024 02:38
Publisher:Elsevier
ISSN:0887-2333
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.tiv.2022.105533
PubMed ID:36473578

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