Comparative carcinogenicities and mutagenicities of vinyl carbamate, ethyl carbamate, and ethyl N-hydroxycarbamate.

Structural modifications of the multipotential carcinogen ethyl carbamate (urethan), CH3CH2—O---CO—-NH2, generally result in dramatic losses of carcinogenic activity, which usually have been assayed by lung adenoma induction and by initiation of skin papillomas in mice (reviewed in Refs. 12 and 20). One exception is ethyl N-hydroxycanbamate, CH3CH2— O—CO—-NHOH, a metabolite of ethyl carbamate (4, 19) with approximately one-half of the tumor-inducing ability of the parent compound (2, 17). This metabolite has greater terato genic and chromosome-damaging activities than does ethyl carbamate (3, 5, 8). The N-hydroxy derivative reacts with cysteine derivatives (4) and with cytosine (21 , 23); ethyl car bamate does not show these chemical reactivities. Because of its somewhat lower carcinogenic activity and its facile reduction to ethyl carbamate in vivo (18, 19), Minvish(19) suggested that ethyl carbamate may be a proximate carcinogen of ethyl Nhydroxycarbamate. In support of this idea, Kaye and Trainin (14) reported that administration of SKF 525A,4 which inhibits the reduction of the N-hydroxy derivative in vivo (19), inhibited the induction of lung adenomas in mice by ethyl N-hydroxycar bamate but not by ethyl carbamate. Likewise, Nomura (25) reported that caffeine administered during the first 36 hr after treatment with the carbamate inhibited induction of these ade nomas by ethyl canbamate but not by ethyl N-hydnoxycarba mate. Recently, we reported that vinyl carbamate, CH2= CH—O—CO—NH2, @5 much more active than ethyl carbamate in initiating skin papillomas and in inducing lung adenomas in mice (7). Vinyl and ethyl canbamatewere not directly mutagenic for Salmonella typhimurium strains TA 1535 and TA 100. However, vinyl carbamate, but not ethyl carbamate, was mu tagenic when the assay system was supplemented with a NADPHand NADH-fortified rat or mouse liver S-i 3 system (7). This mutagenic activity was decreased by the cytochrome P 450 inhibitors DPEA on SKF 525A. Vinyl carbamate was not detected as an in vivo metabolite of ethyl carbamate in mice, although the low 3H:'4Cratio of hepatic DNA isolated from mice given injections of [ethyl-l-14C;l ,2-3H]ethyl carbamate sug gested that the major bound residue was not an intact ethyl group (7). This paper presents comparative data on the carcinogenic and mutagenic activities of vinyl carbamate, ethyl carbamate, and ethyl N-hydroxycarbamate.