Species differences in bile acids II. Bile acid metabolism

Journal of Applied Toxicology : JAT
Rhishikesh ThakareYazen Alnouti

Abstract

One of the mechanisms of drug-induced liver injury (DILI) involves alterations in bile acid (BA) homeostasis and elimination, which encompass several metabolic pathways including hydroxylation, amidation, sulfation, glucuronidation and glutathione conjugation. Species differences in BA metabolism may play a major role in the failure of currently used in vitro and in vivo models to predict reliably the DILI during the early stages of drug discovery and development. We developed an in vitro cofactor-fortified liver S9 fraction model to compare the metabolic profiles of the four major BAs (cholic acid, chenodeoxycholic acid, lithocholic acid and ursodeoxycholic acid) between humans and several animal species. High- and low-resolution liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance imaging were used for the qualitative and quantitative analysis of BAs and their metabolites. Major species differences were found in the metabolism of BAs. Sulfation into 3-O-sulfates was a major pathway in human and chimpanzee (4.8%-52%) and it was a minor pathway in all other species (0.02%-14%). Amidation was primarily with glycine (62%-95%) in minipig and rabbit and it was primarily with taurine (43%-81%) in human, chim...Continue Reading

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Citations

Mar 25, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Yutai LiFrank D Sistare
Mar 21, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qiuhong LinKe Lan
Oct 29, 2020·Journal of Veterinary Diagnostic Investigation : Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc·Kristina WeilerNatali Bauer
Jul 29, 2020·Journal of Lipid Research·Stephanie J ShiffkaMaureen A Kane
Mar 7, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Wushuang ZengKe Lan
May 8, 2021·World Journal of Hepatology·Jawaher Abdullah AlamoudiYazen Alnouti
Jun 1, 2021·Chemico-biological Interactions·Fatemeh Alaei FaradonbehStanislav Micuda
Aug 6, 2021·The Journal of Pharmacology and Experimental Therapeutics·Marlies OortsPieter Annaert
Jun 30, 2019·Gene Expression·Benjamin L Woolbright, Hartmut Jaeschke

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