Toxicological Sciences 59, 82-91 (2001)
Copyright © 2001 by the Society of Toxicology
Carcinogenicity |
Strain-Related Differences in Bioactivation of Vinyl Carbamate and Formation of DNA Adducts in Lungs of A/J, CD-1, and C57BL/6 Mice
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6
Inbred strains of mice exhibit differing susceptibilities to formation of lung tumors induced by procarcinogens including ethyl carbamate (EC) and vinyl carbamate (VC). Strain A/J mice are susceptible, whereas C57BL/6 mice are resistant to lung tumor development. In this study, we tested the hypothesis that differential susceptibilities of A/J, CD-1, and C57BL/6 mice to lung tumor development are associated, in part, with their capacities for VC bioactivation and with the extents of DNA adduct formation. Previous studies have shown that the P450 isozyme CYP2E1 and microsomal carboxylesterases are involved in activation and detoxication of VC, respectively. Bioactivation capacity, as estimated by ratios of p-nitrophenol hydroxylase, a CYP2E1 catalytic marker, to carboxylesterase activities, was greater in control A/J (1.32 ± 0.18 x 10–6) and CD-1 (1.25 ± 0.29 x 10–6) mice than in control C57BL/6 (0.69 ± 0.12 x 10–6) mice. The ratios were reduced in all three strains of mice treated with VC. Covalent binding of [14C-carbonyl]-VC to lung proteins was time- and dose-dependent, and was significantly higher in A/J and CD-1 mice than in C57BL/6 mice. Experiments using 32P-postlabeling/thin-layer chromatography showed formation of the DNA adducts 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine in lungs of mice treated with VC. The DNA adducts were detected at 30 min after treatment, peaked at 60 min, and declined thereafter. Levels of 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine were about 70% higher in A/J and CD-1 mice than in C57BL/6 mice. These results indicated that formation of VC metabolites in these murine strains is linked to their bioactivation capacities, and suggested that this attribute may confer differing susceptibilities to lung tumor development.
Key Words: carboxylesterase; CYP2E1; DNA adducts; epoxide; lung tumors; p-nitrophenol hydroxylase; vinyl carbamate.
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