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-CARBONITRILE
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
The aim of this study was to determine the role of pregnane X receptor
(PXR) in the induction of UDP-glucuronosyltransferases (UGTs) by
pregnenolone-16
-carbonitrile (PCN). Four- to six-month-old male
wild-type and PXR-null mice received control or PCN-treated (1500 ppm) diet
for 21 days. On day 22, livers were taken to prepare microsomes and total RNA
to determine UGT activity and mRNA levels, respectively. In wild-type mice,
PCN treatment significantly increased UGT activities toward bilirubin,
1-naphthol, chloramphenicol, thyroxine, and triiodothyronine. On control diet,
the UGT activities toward the above substrates (except for 1-naphthol) in the
PXR-null mice were significantly higher than those of wild-type mice. However,
UGT activities in PXR-null mice were not increased by PCN. In agreement with
the above findings, mRNA levels of mouse Ugt1a1 and Ugt1a9,
which are involved in the glucuronidation of bilirubin and phenolic compounds,
were increased about 100% in wild-type mice following PCN treatment, whereas
the expression of Ugt1a2, 1a6, and 2b5 was not
affected. In contrast, PCN treatment had no effect on the mRNA levels of these
UGTs in PXR-null mice. Taken together, these results indicate that
PCN treatment induces glucuronidation in mouse liver, and that PXR regulates
constitutive and PCN-inducible expression of some UGTs.
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