3-AMINOBENZAMIDE - EFFECTS ON CYTOCHROME P450-DEPENDENT METABOLISM OFCHEMICALS AND ON THE TOXICITY OF DICHLOBENIL IN THE OLFACTORY MUCOSA

Treatment with 3-aminobenzamide, known as an inhibitor of poly(ADP-rib ose)polymerase, decreased the toxicity and covalent binding of the her bicide dichlobenil (2,6-dichlorobenzonitrile; 12 mg/kg; ip) in the mou se olfactory mucosa. In vitro studies showed that 3-aminobenzamide mar kedly reduced the NADPH-dependent covalent binding of [C-14]dichlobeni l and the hydroxylation of p-nitrophenol which have previously been su ggested to be mediated by a common form of cytochrome P450 (P450) in r at olfactory microsomes (Eriksson and Brittebo, Chem.-Biol. Interact, 94, 183-196, 1995). Furthermore, 3-aminobenzamide markedly reduced the P450-dependent metabolic activation of [H-3]NNK (4-(N-methyl-N-nitros amino) -1-(3-pyridyl)-1-butanone) in rat olfactory microsomes and slig htly decreased the P450 2B1-dependent pentoxyresorufindealkylase activ ity in liver microsomes of phenobarbital-treated rats. The present res ults suggest that 3-aminobenzamide is also an inhibitor of P450 and th at the lack of toxicity of dichlobenil in the olfactory mucosa of 3-am inobenzamide-treated mice is related to a decreased metabolic activati on of dichlobenil at this site. Further experiments showed that there was no evidence for a binding of [C-14]dichlobenil metabolites to calf thymus DNA or a formation of mutagenic dichlobenil metabolites in Ame s' Salmonella assay when dichlobenil was incubated in the presence of homogenates of the olfactory mucosa. Finally, analysis of proteins fro m olfactory microsomes incubated with [C-14]dichlobenil using SDS-PAGE /fluorography revealed a binding of metabolites to all major proteins. Addition of glutathione or the P450-inhibitor metyrapone prevented th e binding, suggesting the formation of relatively stable electrophilic products which can leave the activating enzyme and then unselectively bind to the major olfactory microsomal proteins. (C) 1996 Academic Pr ess, Inc.