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Vol. 29, Issue 11, 1467-1472, November 2001
Department of Pharmacology and Toxicology, University of Kansas
Medical Center, Kansas City, Kansas (J.S., Y.L., S.H., C.D.K.); and
XenoTech LLC, Kansas City, Kansas (A.M.)
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 7
-hydroxylase) gene products in
vivo. Pregnenolone-16-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, 6
-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
6-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 [3H]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.
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