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Carcinogenesis Advance Access published online on March 6, 2007
Carcinogenesis, doi:10.1093/carcin/bgm051
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of vinyl carbamate-induced mutagenicity and clastogenicity by the garlic constituent diallyl sulfone in F1 (Big Blue® x A/J) transgenic mice

Lya G. Hernandez1 and Poh-Gek Forkert1,*

1 Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada

* To whom correspondence should be addressed at: Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6. Tel: 613 533 2854; Fax: 613 533 2566; Email: forkertp{at}post.queensu.ca

Vinyl carbamate (VC) is a metabolite of ethyl carbamate, a naturally-occurring compound found in fermented foods and alcoholic beverages. CYP2E1 mediates the sequential oxidation of ethyl carbamate to VC and subsequently to the VC epoxide, which is believed to be the ultimate carcinogenic species. Here, we have tested the hypothesis that bioactivation of VC by CYP2E1 plays a central role in the development of its mutagenicity and clastogenicity, and further that inhibition of CYP2E1 by diallyl sulfone (DASO2) leads to diminution in their incidences. DASO2 is a garlic constituent that is oxidized by CYP2E1, leading to inactivation of this P450. F1 (Big Blue® x A/J) transgenic mice harboring the lambda cII gene were used for in vivo identification and quantitation of mutations in the lung and small intestine. Mice were pretreated with DASO2 (12.5-200 mg/kg, p.o.), treated 2 h later with VC (60 mg/kg, i.p.), and were sacrificed 4 weeks later. Our results showed that pretreatment of mice with DASO2 at doses of 50 to 200 mg/kg significantly decreased the VC-induced mutant frequencies by 50 to 70%. In the small intestine, pretreatment with 200 mg/kg of DASO2 decreased the mutant frequency by about 40%. Clastogenicity, as assessed by the frequency of micronucleated reticulocytes, were significantly decreased (33-44%) by pretreatment with DASO2 (50 - 200 mg/kg). These results demonstrated that bioactivation of VC by CYP2E1 plays a valid role in the development of mutagenicity and clastogenicity, and further that inhibition of this pathway by DASO2 produces a protective effect.

Received November 11, 2006; revised February 21, 2007; accepted February 27, 2007.


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