3-Ketocholanoic Acid Is the Major in Vitro Human Hepatic Microsomal Metabolite of Lithocholic Acid

Deo, Anand; Bandiera, Stelvio M.

doi:10.1124/dmd.109.027763

Cited by 32 publications

(18 citation statements)

References 34 publications

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“…Previous reports showed 6‐β hydroxylation of LCA and CDCA to MDCA and α‐MCA, respectively, by rat liver microsomes and hepatocytes (Deo & Bandiera, ; Lambiotte & Sjovall, ). In addition, 6‐α hydroxylation of LCA and T‐LCA to HDCA (Deo & Bandiera, ) and T‐HDCA (Czygan et al, ; Trulzsch et al, ) was minimal compared to 12‐α hydroxylation of CDCA into CA (Araya & Wikvall, ).…”

Section: Discussionmentioning

confidence: 99%

Species differences in bile acids II. Bile acid metabolism

Thakare

Alamoudi

Gautam

et al. 2018

J of Applied Toxicology

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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.

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Section: Discussionmentioning

confidence: 99%

Species differences in bile acids II. Bile acid metabolism

Thakare

Alamoudi

Gautam

et al. 2018

J of Applied Toxicology

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“…In another example of the value of gene knockout and humanized mice in exploring the mechanism of hepatotoxicity, mice lacking vitamin D receptor (VDR) expression in intestine and expressing human CYP3A4 in the inestine and liver ( Vdr ΔIEpC /3A4) were used to investigate the role of intestine in modulation of bile acid homeostasis and toxicity in liver [67]. CYP3A4 can metabolize and detoxify LCA in liver [68] and earlier studies revealed that LCA can induced CYP3A4 expression in liver through activating VDR [69]. Compared with LCA-treated Vdr ΔIEpC mice which do not express CYP3A4, LCA-treated Vdr ΔIEpC /3A4 mice that express CYP3A4 showed decreased hepatotoxicity.…”

Section: Bile Acid-induced Hepatotoxicitymentioning

confidence: 99%

Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity

Gonzalez

Fang

2015

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically-modified mouse models and metabolomics. Areas covered Gene knockout mice can be used to determine the enzymes responsible for the metabolism of xenobiotics in vivo and to examine the mechanisms of xenobiotic-induced toxicity. Humanized mouse models are especially important since there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing cytochromes P450 (CYPs) and nuclear receptors including the pregnane X receptor (PXR), the major regulator of xenobiotic metabolism and transport were produced. With genetically-modified mouse models, metabolomics can determine the molecular map of many xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of xenobiotic toxicity and to find early biomarkers for toxicity. Expert opinion Metabolomics and genetically-modified mouse models can be used for the study of xenobiotic metabolism and toxicity by: 1) Comparison of the metabolomics profiles between wild-type and genetically-modified mice, and searching for genotype-dependent endogenous metabolites; 2) Searching for and elucidating metabolites derived from xenobiotics; 3) Discovery of specific alteration of endogenous compounds induced by xenobiotics-induced toxicity.

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“…In the last century, several unusual BAs with hydroxylation sites at C-1, -2, -4, -6, and -19 have been identified by gas chromatographymass spectrometry in humans (Sjövall et al, 2010). Among them, two pathways, 6a-hydroxylation of LCA as hyodeoxycholate (HDCA) (Trülzsch et al, 1974;Araya and Wikvall, 1999;Deo and Bandiera, 2009) and 1b-hydroxylation of DCA as DCA-1b-ol (Gustafsson et al, 1985;Bodin et al, 2005;Hayes et al, 2016), were found to be catalyzed by CYP3A. Thus, HDCA and DCA-1b-ol may be considered tertiary BAs.…”

Section: Introductionmentioning

confidence: 99%

Continuum of Host-Gut Microbial Co-metabolism: Host CYP3A4/3A7 are Responsible for Tertiary Oxidations of Deoxycholate Species

et al. 2019

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The gut microbiota modifies endogenous primary bile acids (BAs) to produce exogenous secondary BAs, which may be further metabolized by cytochrome P450 enzymes (P450s). Our primary aim was to examine how the host adapts to the stress of microbe-derived secondary BAs by P450-mediated oxidative modifications on the steroid nucleus. Five unconjugated tri-hydroxyl BAs that were structurally and/or biologically associated with deoxycholate (DCA) were determined in human biologic samples by liquid chromatographytandem mass spectrometry in combination with enzyme-digestion techniques. They were identified as DCA-19-ol, DCA-6b-ol, DCA-5bol, DCA-6a-ol, DCA-1b-ol, and DCA-4b-ol based on matching in-laboratory synthesized standards. Metabolic inhibition assays in human liver microsomes and recombinant P450 assays revealed that CYP3A4 and CYP3A7 were responsible for the regioselective oxidations of both DCA and its conjugated forms, glycodeoxycholate (GDCA) and taurodeoxycholate (TDCA). The modification of secondary BAs to tertiary BAs defines a host liver (primary BAs)-gut microbiota (secondary BAs)-host liver (tertiary BAs) axis. The regioselective oxidations of DCA, GDCA, and TDCA by CYP3A4 and CYP3A7 may help eliminate host-toxic DCA species. The 19-and 4b-hydroxylation of DCA species demonstrated outstanding CYP3A7 selectivity and may be useful as indicators of CYP3A7 activity. 283

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3-Ketocholanoic Acid Is the Major in Vitro Human Hepatic Microsomal Metabolite of Lithocholic Acid

Cited by 32 publications

References 34 publications

Species differences in bile acids II. Bile acid metabolism

Species differences in bile acids II. Bile acid metabolism

Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity

Continuum of Host-Gut Microbial Co-metabolism: Host CYP3A4/3A7 are Responsible for Tertiary Oxidations of Deoxycholate Species

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