التفاصيل البيبلوغرافية
| العنوان: |
Novel insights into bile acid detoxification via CYP, UGT and SULT enzymes. |
| المؤلفون: |
Kastrinou Lampou, Vlasia1,2,3 (AUTHOR), Poller, Birk1 (AUTHOR), Huth, Felix1 (AUTHOR), Fischer, Audrey2 (AUTHOR), Kullak-Ublick, Gerd A.3,4 (AUTHOR), Arand, Michael5 (AUTHOR), Schadt, Heiko S.2 (AUTHOR), Camenisch, Gian1 (AUTHOR) gian.camenisch@novartis.com |
| المصدر: |
Toxicology in Vitro. Mar2023, Vol. 87, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*BILE acids, *ENZYMES, *METABOLIC detoxification, *HOMEOSTASIS, *LIVER microsomes, *SULFATION, *CYTOCHROME P-450 CYP3A |
| مستخلص: |
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. • CYP3A4 plays a fundamental role in the catabolism, detoxification and clearance of conjugated and unconjugated bile acids. • CYP3A4, UGT1A3/2B7 and SULT2A1 are the main enzymes catalysing BA hydroxylation, glucuronidation and sulfation, respectively. • LCA is the only BA with affinity for all enzymes as a consequence of its high lipophilicity • A comprehensive tool encompassing all important metabolic pathways will significantly improve our understanding of drug-induced cholestasis and DILI. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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