Species differences in bile acids II. Bile acid metabolism

Rhishikesh Thakare, Jawaher Abdullah Alamoudi, Nagsen Gautam, A. David Rodrigues, Yazen Alnouti

Research output: Contribution to journalArticle

4 Citations (Scopus)

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, chimpanzee, dog, hamster, rat and mice. Hydroxylation was highest (13%–80%) in rat and mice followed by hamster, while it was lowest (1.6%–22%) in human, chimpanzee and minipig. C6-β hydroxylation was predominant (65%–95%) in rat and mice, while it was at C6-α position in minipig (36%–97%). Glucuronidation was highest in dog (10%–56%), while it was a minor pathway in all other species (<12%). The relative contribution of the various pathways involved in BA metabolism in vitro were in agreement with the observed plasma and urinary BA profiles in vivo and were able to predict and quantify the species differences in BA metabolism. In general, overall, BA metabolism in chimpanzee is most similar to human, while BA metabolism in rats and mice is most dissimilar from human.

Original languageEnglish (US)
Pages (from-to)1336-1352
Number of pages17
JournalJournal of Applied Toxicology
Volume38
Issue number10
DOIs
StatePublished - Oct 2018

Fingerprint

Bile Acids and Salts
Metabolism
Pan troglodytes
Miniature Swine
Hydroxylation
Rats
Liver
Chemical and Drug Induced Liver Injury
Cricetinae
Lithocholic Acid
Dogs
Chenodeoxycholic Acid
Cholic Acid
Ursodeoxycholic Acid
Metabolome
Taurine
Drug Discovery
Metabolites
Metabolic Networks and Pathways
Pharmaceutical Preparations

Keywords

  • LC–MS/MS
  • bile acids
  • drug-induced liver injury
  • human
  • liver S9 fractions
  • preclinical species

ASJC Scopus subject areas

  • Toxicology

Cite this

Thakare, R., Alamoudi, J. A., Gautam, N., Rodrigues, A. D., & Alnouti, Y. (2018). Species differences in bile acids II. Bile acid metabolism. Journal of Applied Toxicology, 38(10), 1336-1352. https://doi.org/10.1002/jat.3645

Species differences in bile acids II. Bile acid metabolism. / Thakare, Rhishikesh; Alamoudi, Jawaher Abdullah; Gautam, Nagsen; Rodrigues, A. David; Alnouti, Yazen.

In: Journal of Applied Toxicology, Vol. 38, No. 10, 10.2018, p. 1336-1352.

Research output: Contribution to journalArticle

Thakare, R, Alamoudi, JA, Gautam, N, Rodrigues, AD & Alnouti, Y 2018, 'Species differences in bile acids II. Bile acid metabolism', Journal of Applied Toxicology, vol. 38, no. 10, pp. 1336-1352. https://doi.org/10.1002/jat.3645
Thakare, Rhishikesh ; Alamoudi, Jawaher Abdullah ; Gautam, Nagsen ; Rodrigues, A. David ; Alnouti, Yazen. / Species differences in bile acids II. Bile acid metabolism. In: Journal of Applied Toxicology. 2018 ; Vol. 38, No. 10. pp. 1336-1352.
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