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Drug Metabolism and Disposition Fast Forward
First published on February 9, 2007; DOI: 10.1124/dmd.106.013144

0090-9556/07/3505-728-733$20.00
DMD 35:728-733, 2007

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Assessment of Human Pregnane X Receptor Involvement in Pesticide-Mediated Activation of CYP3A4 Gene

Tsutomu Matsubara, Wachiraporn Noracharttiyapot, Takayoshi Toriyabe, Kouichi Yoshinari, Kiyoshi Nagata, and Yasushi Yamazoe

Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (T.M., W.N., T.T., K.Y., K.N., Y.Y.); and Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, the Tohoku University 21st Century "Center of Excellence" Program, Sendai, Japan (T.M., Y.Y.)

Assessment of foreign chemical inducibility on CYP3A4 is necessary to optimize drug therapies. The properties of chemicals such as pesticides, however, are not well investigated. In the present study, properties of various pesticides on human CYP3A4 induction have been tested using HepG2-derived cells stably expressing the CYP3A4 promoter/enhancer (3-1-10 cells) and the human pregnane X receptor (hPXR)-small interfering RNA (siRNA) system. Among the examined pesticides, 13 pesticides were observed to activate the CYP3A4 gene. Surprisingly, pyributicarb was found to increase the CYP3A4 reporter activity at 0.1 to 1 µM more strongly than typical CYP3A4 inducer rifampicin. Expression of hPXR-siRNA clearly diminished the pyributicarb-stimulated CYP3A4 reporter activity in 3-1-10 cells and decreased the endogenous CYP3A4 mRNA levels in HepG2 cells. Pyributicarb caused enhancement of CYP3A4-derived reporter activity in mouse livers introduced with hPXR by adenovirus. These results indicate pyributicarb as a potent activator of CYP3A4 gene, suggesting the existence of pesticides leading to CYP3A4 induction in our environment.

Address correspondence to: Kouichi Yoshinari, Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-aoba 6-3, Aoba-ku, Sendai, Miyagi 980-8578, Japan. E-mail: kyoshina{at}mail.pharm.tohoku.ac.jp




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