3-Aminobenzamide: effects on cytochrome P450-dependent metabolism of chemicals and on the toxicity of dichlobenil in the olfactory mucosa.
Treatment with 3-aminobenzamide, known as an inhibitor of poly(ADP-ribose)polymerease, decreased the toxicity and covalent binding of the herbicide dichlobenil (2,6-dichlorobenzonitrile; 12 mg/kg; i.p.) in the mouse olfactory mucosa. In vitro studies showed that 3-aminobenzamide markedly reduced the NADPH-dependent covalent binding of [14C]dichlobenil and the hydroxylation of p-nitrophenol which have previously been suggested to be mediated by a common form of cytochrome P450 (P450) in rat olfactory microsomes (Eriksson and Brittebo, Chem.-Biol. Interact. 94,183-196, 1995). Furthermore, 3-aminobenzamide markedly reduced the P450-dependent metabolic activation of [3H]NNK (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone) in rat olfactory microsomes and slightly decreased the P450 2B1-dependent pentoxyresorufindealkylase activity in liver microsomes of phenobarbital-treated rats. The present results suggest that 3-aminobenzamide is also an inhibitor of P450 and that the lack of toxicity of dichlobenil in the olfactory mucosa of 3-aminobenzamide-treated mice is related to a decreased metabolic activation of dichlobenil at this site. Further experiments showed that there was no evidence for a binding of [14C]dichlobenil metabolites to calf thymus DNA or a formation of mutagenic dichlobenil metabolites in Ames' Salmonella assay when dichlobenil was incubated in the presence of homogenates of the olfactory mucosa. Finally, analysis of proteins from olfactory microsomes incubated with [14C]dichlobenil using SDS-PAGE/fluorography revealed a binding of metabolites to all major proteins. Addition of glutathione or the P450-inhibitor metyrapone prevented the 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.
Eriksson
C
C
Department of Pharmacology and Toxicology, Uppsala Biomedical Center, SLU, Sweden.
Busk
L
L
Brittebo
E B
EB
D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D001711:Biotransformation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D006540:Herbicides / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009570:Nitriles; D009596:Nitrophenols / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006540:Herbicides; D009570:Nitriles; D009596:Nitrophenols; D009602:Nitrosamines; D011725:Pyridines; C013109:metapyrone; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C025160:3-aminobenzamide; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; C055869:dichlobanil; C024836:4-nitrophenol