Bioactivation of the cyanide antidote 4-aminopropiophenone (4-PAPP) by human and rat hepatic microsomal enzymes: effect of inhibitors

The bioactivation of the cyanide antidote methaemoglobin former 4-aminopropiophenone (4-PAPP) was studied using rat and human microsomes. With rat liver and NADPH in single and two-compartment systems, dapsone and benzocaine were more potent methaemoglobin generators compared with 4-PAPP. In the single compartment studies, the order of potency of inhibition of 4-PAPP-mediated methaemoglobin formation was cimetidine (1.5 mM)>isoniazid (500 μM)/diethyldithiocarbamate (DDC, 1 mM)>erythromycin (500 μM). Human liver microsomal activation of 4-PAPP in the two-compartment system was partially inhibited by both DDC and cimetidine. These preliminary studies suggest that 4-PAPP may be metabolised by CYP 2C11, 2E1 and 3A in the rat and CYP 2C, 2E1 and probably 3A4 in man.