A monoclonal antibody against cytochrome P-450 enhances mutagen activation of N-nitrosodimethylamine by mouse liver S9: studies on the mode of action.
The effect of the monoclonal antibody MAb 2-66-3, directed against the major rat liver phenobarbital (PB)-induced cytochrome P-450 (P-450), on the S9-mediated mutagenicity of N-nitrosodimethylamine (DMN) in Salmonella typhimurium strain TA1530 was studied using liver S9 from PB-treated mice. This MAb enhanced approximately 2-fold S9-mediated mutagenicity of DMN but inhibited both its N-demethylation and N-denitrosation by 50%. Thus MAb-mediated enhancement of DMN mutagenesis does not result from altered activation/inactivation pathways, both known to involve P-450 isozymes. DMSO, a hydroxyl radical (HO.) scavenger and desferrioxamine, an inhibitor of HO.-dependent reactions, quenched the MAb-mediated enhancement of DMN mutagenesis, implicating the HO.-dependent activation of DMN to mutagenic species. As a mechanism, we propose that the binding of this MAb to P-450 isozyme implicated in DMN metabolism decreases the functional coupling between the reductase and the P-450 complex, leading to an increased electron flow from the reductase towards molecular oxygen to form reduced oxygen species (HO.) at the expense of the monooxygenase functions.
Malaveille
C
C
International Agency for Research on Cancer, Lyon, France.
Brun
G
G
Park
S S
SS
Gelboin
H V
HV
Bartsch
H
H
D000818:Animals; D000911:Antibodies, Monoclonal; D003043:Cocarcinogenesis; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004128:Dimethylnitrosamine / Q000494:pharmacology*; D007527:Isoenzymes / Q000276:immunology; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009152:Mutagenicity Tests; D010634:Phenobarbital / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects
D000911:Antibodies, Monoclonal; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D004128:Dimethylnitrosamine; D004121:Dimethyl Sulfoxide; D010634:Phenobarbital