Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor
| Autor: | J, Staudinger, Y, Liu, A, Madan, S, Habeebu, C D, Klaassen |
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| Rok vydání: | 2001 |
| Předmět: |
Mice
Knockout Pregnenolone Carbonitrile Receptors Steroid Pregnane X Receptor Receptors Cytoplasmic and Nuclear Oxidoreductases N-Demethylating Organic Anion Transporters Sodium-Independent Xenobiotics Bile Acids and Salts Mice Cytochrome P-450 Enzyme System Hepatocytes Microsomes Liver Animals Cytochrome P-450 CYP3A Homeostasis Aryl Hydrocarbon Hydroxylases Hepatomegaly |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 29(11) |
| ISSN: | 0090-9556 |
| Popis: | Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased understanding of the molecular basis of many drug-drug interactions. Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholesterol 7alpha-hydroxylase) gene products in vivo. Pregnenolone-16alpha-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3A activity, 6beta-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6beta-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo. |
| Databáze: | OpenAIRE |
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