Carcinogenesis Advance Access originally published online on March 6, 2007
Carcinogenesis 2007 28(8):1824-1830; doi:10.1093/carcin/bgm051
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Inhibition of vinyl carbamate-induced mutagenicity and clastogenicity by the garlic constituent diallyl sulfone in F1 (Big Blue® x A/J) transgenic mice
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada
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Vinyl carbamate (VC) is a metabolite of ethyl carbamate (EC), a naturally occurring compound found in fermented foods and alcoholic beverages. CYP2E1 mediates the sequential oxidation of EC to VC and subsequently to the vinyl carbamate 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 
cII gene were used for in vivo identification and quantitation of mutations in the lung and small intestine. Mice were pre-treated with DASO2 (12.5–200 mg/kg, p.o.), treated 2 h later with VC (60 mg/kg, i.p.) and were killed 4 weeks later. Our results showed that pre-treatment of mice with DASO2 at doses of 50–200 mg/kg significantly decreased the VC-induced mutant frequencies (MFs) by 50–70%. In the small intestine, pre-treatment with 200 mg/kg of DASO2 decreased the MF by 
40%. Clastogenicity, as assessed by the frequency of micronucleated reticulocytes, was significantly decreased (33–44%) by pre-treatment 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.
Abbreviations: DASO2, diallyl sulfone; 
dAS, 1,N6-ethenodeoxyadenosine; EC, ethyl carbamate; EDTA, ethylenediaminetetraacetic acid; MF, mutant frequency; PCR, polymerase chain reaction; VC, vinyl carbamate; VCO, vinyl carbamate epoxide
Received November 11, 2006; revised February 21, 2007; accepted February 27, 2007.