Abstract
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.
Footnotes
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This work was supported in part by grant-in-aid from the Ministry of Education, Culture, Sports, Sciences, and Technology and from the Ministry of Health, Labour, and Welfare of Japan, and by Research on Health Sciences focusing on Drug Innovation from The Japan Health Sciences Foundation.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.013144.
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ABBREVIATIONS: PXR, pregnane X receptor; RIF, rifampicin; CTZ, clotrimazole; CAR, constitutive androstane receptor; VDR, vitamin D receptor; siRNA, small interfering RNA; hPXR, human pregnane X receptor; VD3,1α,25-dihydroxyvitamin D3; TCID50, 50% titer culture infectious dose; PCR, polymerase chain reaction; mPXR, mouse pregnane X receptor; MOI, multiplicity of infection; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; EPN, O-ethyl O-4-nitrophenyl phenylphosphonothioate; PCN, pregnenolone 16α-carbonitrile; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; RT-PCR, reverse transcription-polymerase chain reaction.
- Received September 28, 2006.
- Accepted February 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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Assessment of Human Pregnane X Receptor Involvement in Pesticide-Mediated Activation of CYP3A4 Gene
