Role of metabolic activation in the sister chromatid exchange-inducing activity of ethyl carbamate (urethane) and vinyl carbamate.

Ethyl carbamate (EC, urethane) at 10(-2) M concentration induced more sister chromatid exchanges (SCEs) in cultured human peripheral blood lymphocytes in the absence of S9 mix than did 10(-2) M vinyl carbamate (VC), a possible proximate carcinogenic metabolite (Dahl et al., 1978) of EC. VC itself doubled SCE frequency over the control. In the presence of native S9 mix from Aroclor-induced rat liver, the SCE-inducing activity of VC was highly increased whereas that of EC was suppressed. This opposite effect of S9 mix on VC and EC seems to be due to two different factors. Activation of VC by the S9 fraction seems to be due to the presence of mixed-function oxidases in the S9 mix, because neither the native S9 fraction in the absence of co-factors nor the heat-inactivated S9 fraction in the incubation mixture led to the activation of VC. Deactivation of EC by S9 mix, on the other hand, seems to involve the presence of excess protein and/or substances of low molecular weight in the incubation mixture, because this deactivating effect did not change considerably when the S9 fraction was supplied in the absence of co-factors or when it originated from non-induced rat liver. Heat denaturation of the S9 fraction led to an increased deactivating effect on the SCE-inducing ability of EC. This result is in line with the assumption that reactive -SH groups in the S9 protein are at least partly responsible for the deactivation of EC by S9. Heat denaturation of the S9 fraction led to an about 1.5-fold increase in reactive -SH groups.