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Carcinogenesis Advance Access originally published online on May 5, 2006
Carcinogenesis 2006 27(10):2090-2095; doi:10.1093/carcin/bgl064
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Different activation patterns of rat xenobiotic metabolism genes by two constituents of garlic

Ping Zhang, Marie-Louise Noordine, Claire Cherbuy, Pierre Vaugelade, Jean Marc Pascussi1, Pierre-Henri Duée and Muriel Thomas*

Laboratoire de Nutrition et de Sécurité Alimentaire, INRA Domaine de Vilvert, 78352 Jouy en Josas, France
1 INSERM U128, Physiopathologie Hépatique 1919, Route de Mende, 34293 Montpellier Cedex 5, France

*To whom correspondence should be addressed at: Tel: 33 1 34 65 28 35; Fax: 33 1 34 65 23 11; Email: Muriel.thomas{at}jouy.inra.fr

Diallyl sulfide (DAS) and diallyl disulfide (DADS) are natural components that could account for the anticarcinogenic properties of garlic, at least in part, through the activation of xenobiotic detoxifying metabolism. The aim of this work was to describe the effect of DAS and DADS on xenobiotic-related gene expressions and to study molecular mechanisms relaying DAS effect. We describe the different effects of DAS and DADS on hepatic CYP2B1/2, CYP3A and epoxide hydrolase (EpH) mRNAs in rats, in terms of activation profile, doses and kinetics. The activation profile varied with the mode of chemical administration, i.e. gastric infusion or intraperitoneal (i.p.) injection. Using gastric infusion, DAS and DADS proved different efficiencies at enhancing the mRNA level of the three drug-metabolizing enzymes. After an i.p. administration, we observed a specific activation of CYP2B1/2 gene by DAS. The DAS-mediated CYP2B1/2 activation occurred at transcriptional level and through an okadaic acid-sensitive pathway. In rat livers, a short sequence (NR1) derived from the CYP2B1/2 promoter was stimulated by DAS and we observed a nuclear accumulation of a DNA–protein complex binding NR1. Because constitutively activated receptor (CAR) is a major transcription factor driving the xenobiotic-induced stimulation of CYP2B1/2 through NR1, the role of CAR as a preferential mediator of DAS effect is discussed.


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