Identification of Human Hepatic Cytochrome P450 Enzymes Involved in the Biotransformation of Cholic and Chenodeoxycholic Acid

Deo, Anand; Bandiera, Stelvio M.

doi:10.1124/dmd.108.022194

Cited by 48 publications

(31 citation statements)

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“…Peaks with retention times of 19.5 min (m/z of 391) and 14.5 min (m/z 389), which corresponded to chenodeoxycholic acid and 7-ketolithocholic acid, respectively, were determined to be minor contaminants of lithocholic acid, as previously reported (Deo and Bandiera, 2008a). We did not detect metabolites of chenodeoxycholic acid (Deo and Bandiera, 2008b) in the present study.…”

Section: Resultscontrasting

confidence: 35%

“…As reported, 3-dehydrocholic acid was the only metabolite of cholic acid, and 7␣-hydroxy-3-oxo-5␤-cholanoic acid was the major metabolite of chenodeoxycholic acid (Deo and Bandiera, 2008b), whereas 3-ketocholanoic acid was the major metabolite of lithocholic acid in this study. Formation of all three metabolites was mediated by CYP3A4.…”

Section: Discussionmentioning

confidence: 48%

“…Comparison of metabolite profiles of lithocholic acid with those of cholic acid and chenodeoxycholic acid (Deo and Bandiera, 2008b) reveals that formation of 3-oxo metabolites is the dominant biotransformation pathway for bile acids in human liver microsomes. As reported, 3-dehydrocholic acid was the only metabolite of cholic acid, and 7␣-hydroxy-3-oxo-5␤-cholanoic acid was the major metabolite of chenodeoxycholic acid (Deo and Bandiera, 2008b), whereas 3-ketocholanoic acid was the major metabolite of lithocholic acid in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Comparison of V max and K m values, obtained using human liver microsomes, for chenodeoxycholic and cholic acid metabolite formation (Deo and Bandiera, 2008b) revealed that lithocholic acid was biotransformed as readily as chenodeoxycholic acid and slower than cholic acid but at lower substrate concentrations. In contrast, the rate of lithocholic acid biotransformation by rat liver microsomes was much greater than by human liver microsomes.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Formation of hyodeoxycholic acid was a minor pathway (Deo and Bandiera, 2008a). Results from our recent investigation of 3␣,7␣,12␣-trihydroxy-5␤-cholan-24-oic (cholic) acid and chenodeoxycholic acid biotransformation by human liver microsomes (Deo and Bandiera, 2008b) suggest that neither 6␣-hydroxylation nor 6␤-hydroxylation would be the preferred P450-catalyzed oxidation pathway for lithocholic acid in human hepatic microsomes. A more thorough investigation of lithocholic acid biotransformation, including the contribution of P450 enzymes other than CYP3A4, is needed to test this hypothesis and to resolve the divergent metabolite profiles reported to date.…”

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

Deo¹,

Bandiera²

2009

Drug Metab Dispos

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ABSTRACT:3␣-Hydroxy-5␤-cholan-24-oic (lithocholic) acid is a relatively minor component of hepatic bile acids in humans but is highly cytotoxic. Hepatic microsomal oxidation offers a potential mechanism for effective detoxification and elimination of bile acids. The aim of the present study was to investigate the biotransformation of lithocholic acid by human hepatic microsomes and to assess the contribution of cytochrome P450 (P450) enzymes in human hepatic microsomes using human recombinant P450 enzymes and chemical inhibitors. Metabolites were identified, and metabolite formation was quantified using a liquid chromatography/mass spectrometry-based assay. Incubation of lithocholic acid with human liver microsomes resulted in the formation of five metabolites, which are listed in order of their rates of formation: 3-oxo-5␤-cholan-24-oic (3-ketocholanoic) acid, 3␣,6␣-dihydroxy-5␤-cholan-24-oic (hyodeoxycholic) acid, 3␣,7␤-dihydroxy-5␤-cholan-24-oic (ursodeoxycholic) acid, 3␣,6␤-dihydroxy-5␤-cholan-24-oic (murideoxycholic) acid, and 3␣-hydroxy-6-oxo-5␤-cholan-24-oic (6-ketolithocholic) acid. 3-Ketocholanoic acid was the major metabolite, exhibiting apparent K m and V max values of 22 M and 336 pmol/ min/mg protein, respectively. Incubation of lithocholic acid with a of human recombinant P450 enzymes revealed that all five metabolites were formed by recombinant CYP3A4. Chemical inhibition studies with human liver microsomes and recombinant P450 enzymes confirmed that CYP3A4 was the predominant enzyme involved in hepatic microsomal biotransformation of lithocholic acid. In summary, the results indicate that oxidation of the third carbon of the cholestane ring is the preferred position of oxidation by P450 enzymes for lithocholic acid biotransformation in humans and suggest that formation of lithocholic acid metabolites leads to enhanced hepatic detoxification and elimination.

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Section: Resultscontrasting

confidence: 35%

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

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confidence: 99%

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

Deo¹,

Bandiera²

2009

Drug Metab Dispos

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Effect of bile and lipids on the stereoselective metabolism of halofantrine by rat everted‐intestinal sacs

Patel¹,

Korashy²,

El‐Kadi³

et al. 2009

Chirality

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The everted rat intestinal-sac model was utilized to assess the effect of post-prandial conditions on the stereoselective intestinal metabolism of halofantrine to its active metabolite desbutylhalofantrine. Everted intestinal sacs were incubated with (+/-)-halofantrine HCl in the presence of simulated bile solution (containing lecithin, lipase and cholesterol) and lipids to mimic post-prandial conditions in the small intestine. The halofantrine enantiomer concentrations in intestinal sacs were relatively constant in the presence of bile, but decreased significantly on addition of lipids to the incubation media. Formation of desbutylhalofantrine enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in desbutylhalofantrine:halofantrine ratio of (-) enantiomers. Pre-treatment of rats with peanut oil had no significant effect on desbutylhalofantrine formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal cytochrome P450. Addition of extra cholesterol to the bile incubations caused a significant increase in tissue halofantrine and desbutylhalofantrine concentrations, which as for lower cholesterol, were diminished on addition of other lipids. The results were consistent with previous in vivo evaluations showing that the desbutylhalofantrine to halofantrine ratio was decreased by the ingestion of a high fat meal.

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Ratio of Conjugated Chenodeoxycholic to Muricholic Acids is Associated with Severity of Nonalcoholic Steatohepatitis

Chen

Zheng

Liu

et al. 2019

Obesity

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Objective Bile acids (BAs) are important molecules in the progression of nonalcoholic fatty liver disease. This study aimed to investigate BA profile alterations in Chinese nonalcoholic steatohepatitis (NASH) patients. Methods BA profiles in serum and liver tissues were determined by ultraperformance liquid chromatography coupled to tandem mass spectrometry in patients from two different clinical centers. Results A total of 134 participants were enrolled in this study to serve as the training (n = 87) and validation (n = 47) cohorts. The ratio of circulating conjugated chenodeoxycholic acids to muricholic acids (P = 0.001) was elevated from healthy controls to non‐NASH individuals to NASH individuals in a stepwise manner in the training cohort and was positively associated with the histological severity of NASH: steatosis (R2 = 0.12), lobular inflammation (R2 = 0.12), ballooning (R2 = 0.11), and fibrosis stage (R2 = 0.18). The ratio was elevated in the validation cohort of NASH patients (P < 0.001), and it was able to predict NASH (area under the receiver operating characteristic curve: 75%) and significant fibrosis (area under the receiver operating characteristic curve: 71%) in these two cohorts. Moreover, this elevated ratio and impaired farnesoid X receptor signaling were found in the NASH liver. Conclusions Altered BA profile in NASH is closely associated with the severity of liver lesions, and it has the potential for predicting NASH development.

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Identification of Human Hepatic Cytochrome P450 Enzymes Involved in the Biotransformation of Cholic and Chenodeoxycholic Acid

Cited by 48 publications

References 40 publications

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

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

Effect of bile and lipids on the stereoselective metabolism of halofantrine by rat everted‐intestinal sacs

Ratio of Conjugated Chenodeoxycholic to Muricholic Acids is Associated with Severity of Nonalcoholic Steatohepatitis

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