Inhibition of vinyl carbamate-induced mutagenicity and clastogenicity by the garlic constituent diallyl sulfone in F1 (Big Blue x A/J) transgenic mice.
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 (DASO(2)) leads to diminution in their incidences. DASO(2) is a garlic constituent that is oxidized by CYP2E1, leading to inactivation of this P450. F(1) (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 pre-treated with DASO(2) (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 DASO(2) 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 DASO(2) decreased the MF by approximately 40%. Clastogenicity, as assessed by the frequency of micronucleated reticulocytes, was significantly decreased (33-44%) by pre-treatment with DASO(2) (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 DASO(2) produces a protective effect.
Hernandez
Lya G
LG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Forkert
Poh-Gek
PG
D000498:Allyl Compounds / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003433:Crosses, Genetic; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005737:Garlic; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D009153:Mutagens; D013450:Sulfones / Q000008:administration & dosage* / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity
D000498:Allyl Compounds; D009153:Mutagens; D013450:Sulfones; C068327:diallyl sulfone; D014520:Urethane; C017963:vinyl carbamate; D004247:DNA; D019392:Cytochrome P-450 CYP2E1