Inhibition of the metabolism of urethane by ethanol

Ethanol has been shown to inhibit the localization of [ethyl-1-14C] urethane in the male mouse, but the effect of ethanol on the metabolism of urethane has not been clarified. Consequently, the concentration of unchanged urethane was determined in the blood of male mice up to 11 hr after oral administration of urethane with or without ethanol. A high and constant blood level of urethane persisted for 8 hr after the administration of an ethanolic solution of [ethyl-1-14C] urethane (125 mumol/kg, 10 muCi/20 g of mouse, 5 g of ethanol per kg, po); the blood level of ethanol was at or above 150 mg/dl during these 8 hr. In contrast, rapid clearance of radioactivity was observed in mice treated with [ethyl-1-14C]urethane dissolved in water. Coadministration of ethanol with urethane decreased the rate of 14CO2 expiration; furthermore, covalent binding with liver protein was delayed about 8 hr and was less than that in the group treated with urethane in water. The metabolism of urethane and production of 14CO2 from [carbonyl-14C]urethane by mouse liver homogenate in vitro were inhibited by the presence of ethanol (greater than 10 mM); these concentrations of ethanol in vitro are about the same as those that are inhibitory in vivo, but the extent of inhibition suggests that the liver is not the only site of metabolism of urethane. These results indicate that ethanol can inhibit the initial metabolism of urethane, prevent the formation of active metabolites, and allow urethane to persist in blood.