Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27 Mice but Not in Cerebrotendinous Xanthomatosis

Honda, Akira; Salen, Gerald; Matsuzaki, Yasushi; Batta, Ashok K.; Xu, Guowang; Leitersdorf, Eran; Tint, G. Stephen; Erickson, Sandra K.; Tanaka, Naomi; Shefer, Sarah

doi:10.1074/jbc.m103025200

Cited by 74 publications

(81 citation statements)

References 46 publications

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“…4B). Both 7␣-hydroxy-4-cholesten-3-one (2) and 5␤-cholestan-3␣, 7␣, 12␣-triol (3) are present in the livers of Cyp27a1 Ϫ/Ϫ mice at low micromolar concentrations (6), which is consistent with a role for these compounds as endogenous PXR agonists. The increased sensitivity of mouse PXR to 7␣-hydroxy-4-cholesten-3-one (2), 4-cholesten-3-one (4), and 5␤-cholestan-3␣,7␣,12␣-triol (3) may explain in part why CYP3A expression is induced in Cyp27a1 Ϫ/Ϫ mice but not in human CTX.…”

Section: Figsupporting

confidence: 57%

“…1). Other groups have recently demonstrated that the enzymatic activity of CYP3A11, which serves as a 5␤-cholestan-3␣,7␣,12␣-triol hydroxylase, is markedly up-regulated in the livers of Cyp27a1 Ϫ/Ϫ mice (7,21).…”

Section: Resultsmentioning

confidence: 99%

“…Cyp27a1 Ϫ/Ϫ mice reproduce only a few of the biochemical changes seen in human CTX. In particular, there are only trace levels of 25-hydroxylated bile alcohols, far less than those detected in humans (6,7), and cholesterol biosynthesis is enhanced in various organs (8). Also in contrast to humans, these mice do not show evidence of xanthomas, accumulation of excessive cholesterol or cholestanol, or neural dysfunction.…”

mentioning

confidence: 90%

“…These metabolites can be either excreted from the body in the bile or urine or converted to CA. Notably, CYP3A activity does not appear to be increased in human CTX, suggesting a potential explanation for the dichotomy in CYP27A1 Ϫ/Ϫ phenotypes between mice and humans (7,10).…”

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confidence: 99%

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Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Goodwin

Gauthier

Umetani

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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179

128

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Sterol 27-hydroxylase (CYP27A1) is required for bile acid synthesis by both the classical and alternate pathways. Cyp27a1 ؊/؊ mice exhibit a dramatic increase in the activity of cytochrome P450 3A (CYP3A), which catalyzes side-chain hydroxylations of bile acid intermediates, thereby facilitating their excretion in the bile and urine. We examine the role of the nuclear xenobiotic receptor PXR (pregnane X receptor) in this process. We demonstrate that expression of Cyp3a11 and other established PXR target genes is increased in the Cyp27a1 ؊/؊ mice. WhenCyp27a1 ؊/؊ mice are fed a diet containing either cholic acid or chenodeoxycholic acid, expression of CYP7A1, which catalyzes the rate-limiting step in bile acid biosynthesis, is strongly suppressed. In parallel, the induction of Cyp3a11 observed in these mice is reversed, suggesting that bile acid intermediates serve as PXR activators. In support of this hypothesis, three potentially toxic sterols (7␣-hydroxy-4-cholesten-3-one, 5␤-cholestan-3␣,7␣,12␣-triol, and 4-cholesten-3-one), including two that are known to accumulate in Cyp27a1 ؊/؊ mice, are efficacious activators of mouse PXR. All three compounds are more potent activators of mouse PXR than of human PXR, which may explain in part why humans who lack functional CYP27A1 do not display a corresponding increase in CYP3A activity and are stricken with the disease cerebrotendinous xanthomatosis. Taken together, these results reveal the existence of a feedforward regulatory loop by which potentially toxic bile acid intermediates activate PXR and induce their own metabolism. In addition, this study demonstrates that animal models with alterations in gene expression can be used to identify endogenous ligands for orphan nuclear receptors.

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Section: Figsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 90%

mentioning

confidence: 99%

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Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Goodwin

Gauthier

Umetani

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

179

128

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“…Additionally, in humans, CYP3A4 is the predominant enzyme responsible for 25-and 26-hydroxylations of 5␤-cholestane-3␣7␣12␣-triol and 27-hydroxylation of 5␤-cholestane-3␣7␣12␣,25-tetrol in the classic bile acid biosynthetic pathway (24, 25). In mice, Cyp3a11 is responsible for these microsomal side chain hydroxylations (25).…”

Section: Discussionmentioning

confidence: 99%

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

Stedman

Robertson

Coulter

et al. 2004

Journal of Biological Chemistry

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Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5 regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6␤-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

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Human Cytochrome P450 Enzymes

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Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27 Mice but Not in Cerebrotendinous Xanthomatosis

Cited by 74 publications

References 46 publications

Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

Human Cytochrome P450 Enzymes

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