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Drug Metabolism and Disposition Fast Forward
First published on October 4, 2004; DOI: 10.1124/dmd.104.001537

0090-9556/05/3301-55-59$20.00
DMD 33:55-59, 2005

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BISPHENOL A GLUCURONIDATION AND EXCRETION IN LIVER OF PREGNANT AND NONPREGNANT FEMALE RATS

Hiroki Inoue, Akio Tsuruta, Satoko Kudo, Takako Ishii, Yusuke Fukushima, Hidetomo Iwano, Hiroshi Yokota, and Seiyu Kato

Department of Veterinary Physiology (H.In., A.T., S.Ku., T.I., Y.F., S.Ka.) and Veterinary Biochemistry (H.Iw., H.Y.), School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan

In male rats challenged with the environmental estrogen bisphenol A, the compound is highly glucuronidated in the liver and is excreted largely into the bile. Given that in pregnancy the microsomal glucuronidation toward bisphenol A is attenuated, we hypothesized that elimination of bisphenol A from the liver may be reduced in pregnancy. This study was conducted to trace the elimination of bisphenol A in female rats, especially in pregnancy. In Sprague-Dawley rats, 1.5 µmol of bisphenol A was perfused into the liver via the portal vein. In both the male and the nonpregnant female, the infused bisphenol A was glucuronidated, then the resultant glucuronide was excreted mainly into the bile. In pregnant rats, however, bilious excretion of bisphenol A glucuronide was 60% of that observed in nonpregnant rats, and venous excretion increased reciprocally. During 1-h perfusion, total excretion of the glucuronide from the liver of male, nonpregnant female, and pregnant rats was 889.5 ± 69.6, 1256.7 ± 54.8, and 1038.8 ± 33.3 nmoles, respectively. In Eisai hyperbilirubinemic rats (EHBR), perfusion of the liver with bisphenol A enabled us to determine that multidrug resistance-associated protein (MRP)2-mediating transport is the mechanism behind excretion of the glucuronide into the bile. The expression of MRP2 has been reported to be noticeably reduced in pregnancy. These results suggest that bisphenol A elimination by hepatic glucuronidation is slightly less in pregnancy than in non-pregnancy and that in pregnancy, more bisphenol A glucuronide is eliminated to the vein because of reduced MRP2 expression.

Address correspondence to: Seiyu Kato, Department of Veterinary Physiology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, 069-8501 Japan. E-mail: kato{at}rakuno.ac.jp




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