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

摘要

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? × A/J) transgenic mice harboring the λ 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.