1,N6-ethenoadenosine formation, mutagenicity and murine tumor induction as indicators of the generation of an electrophilic epoxide metabolite of the closely related carcinogens ethyl carbamate (urethane) and vinyl carbamate.
Previous studies from this laboratory showed that (i) vinyl carbamate (VC) was much more carcinogenic than ethyl carbamate (EC) and that both carbamates induced the same spectrum of tumors in mice and rats, (ii) adducts of [14C]- or [3H]1,N6-ethenoadenosine and [14C]- or [3H]3,N4-ethenocytidine e were formed in the hepatic RNA of infant male B6C3F1 mice administered [1-14C]ethyl or [1,2-3H]ethyl EC and (iii) VC formed much more of the 1,N6-ethenoadenosine (epsilon Ado) adduct in the hepatic RNA and the 7-(2-oxoethyl)-guanine adduct in the hepatic DNA of mice than did EC. By analogy to the similar results of earlier studies by other investigators on the related carcinogen vinyl chloride, the above data suggested that VC epoxide was a reactive electrophilic metabolite of these carbamates. In the present studies, VC, but not EC, was found to be oxidized by 3-chloroperbenzoic acid to a derivative that reacted with adenosine to form epsilon Ado. Far more of this etheno nucleoside was formed from VC than from EC when these carbamates were metabolized by cofactor-fortified mouse liver microsomes in the presence of adenosine. Sodium diethyldithiocarbamate strongly inhibited these microsomal reactions and the formation of epsilon Ado in the hepatic RNA of mice administered either carbamate. Likewise, the i.p. preadministration of deithyldithiocarbamate markedly inhibited the induction of tumors by single i.p. doses of EC or VC in the livers of infant male B6C3F1 mice and in the livers, lungs and Harderian glands of infant female B6C3F1 mice. This inhibitor also considerably reduced lung tumor induction by VC in adult female A/Jax mice. 2-(2,4-Dichloro-6-phenyl) phenoxyethyl amine, a cytochrome P450 inhibitor, reduced the carcinogenicity of low doses of EC but appeared to increase the carcinogenicity of low doses of VC. The mutagenicity of VC for Salmonella typhimurium TA1535 in the presence of a hepatic activating system was greatly reduced by these inhibitors. The data from all these studies are consistent with the proposal that VC epoxide is an ultimate electrophilic and carcinogenic metabolite of EC and VC in the mouse.
McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison 53706.
M T
MT
Leithauser
A
A
Liem
B C
BC
Stewart
E C
EC
Miller
J A
JA
Miller
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D004050:Ditiocarb / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008175:Lung Neoplasms / Q000139:chemically induced; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012854:Sister Chromatid Exchange / Q000187:drug effects; D014520:Urethane / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D009153:Mutagens; C000939:2,4-dichloro-6-phenylphenoxyethylamine; C007640:1,N(6)-ethenoadenosine; D014520:Urethane; D012313:RNA; C017963:vinyl carbamate; D004050:Ditiocarb; D011078:Polychlorinated Biphenyls; D000241:Adenosine