Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.
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.
Staudinger
J
J
Department of Pharmacology and Toxicology, University of Kansas Medical Center, Breidenthal Building, Kansas City, KS 66160-7417, USA.
Liu
Y
Y
Madan
A
A
Habeebu
S
S
Klaassen
C D
CD
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000633:toxicity; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015262:Xenobiotics / Q000378:metabolism*
D001647:Bile Acids and Salts; D029362:Organic Anion Transporters, Sodium-Independent; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C490281:Slc22a7 protein, mouse; D015262:Xenobiotics; D011285:Pregnenolone Carbonitrile; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating