Mechanisms of lung tumorigenesis by ethyl carbamate and vinyl carbamate.
Vinyl carbamate (VC) and ethyl carbamate (EC) induce the formation of lung tumors. The mechanism involves a two-step oxidation of EC to VC and VC to an epoxide, both of which are mediated mainly by CYP2E1. Interaction of the epoxide with DNA leads to the formation of DNA adducts, including 1,N(6)ethenodeoxyadenosine and 1,N(4)-ethenodeoxycytidine. The production of DNA adducts correlated with capacities for the bioactivation of VC, which are higher in the lungs of A/J than in C57BL/6 mice. Importantly, CYP2E1 is higher in the lungs of A/J than in C57BL/6 mice. Studies using F(1) (Big Blue x A/J) transgenic mice revealed the formation of mutations in the lambda cII gene after treatment with VC. Mutations induced by VC were mainly A:T-->G:C transitions and A:T-->T:A transversions, while mutations induced by EC were mainly G:C-->A:T transitions. An EC dose that was 17-fold higher than that for VC was required to produce a similar level of mutant frequency in the lung. Pretreatment of mice with the CYP2E1 inhibitor, diallyl sulfone, significantly inhibited the mutant frequencies induced by VC. Mutations in the endogeneous Kras2 gene were found in codon 61 of exon 2 and were identified as A:T transversions and A-->G transitions in the second base and A-->T transversions in the third base. These mutations were reduced by treatment of mice with diallyl sulfone before VC and coincided with a reduction in the number of lung tumors with Kras2 mutations. These findings affirmed that the metabolism of EC and VC is a prerequisite for, or at least substantially contributes to, initiation of the cascade of events leading to lung tumor formation.
Forkert
Poh-Gek
PG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity; D018736:DNA Adducts / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D053858:Metabolic Networks and Pathways; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology; D014520:Urethane / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*
D000498:Allyl Compounds; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D013450:Sulfones; C068327:diallyl sulfone; D014520:Urethane; C017963:vinyl carbamate; C064746:vinyl carbamate epoxide