title: Superoxide dismutase-mediated reversible conversion of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole, the N-hydroxy derivative of Trp-P-2, into its nitroso derivative.
abstract: Aerobic oxidation of 3-hydroxyamino-1-methyl-5H-pyrido-[4,3-b]indole [Trp-P-2(NHOH)] in neutral aqueous solution was greatly accelerated by copper-zinc superoxide dismutase (SOD). The major product in this SOD-mediated reaction was identified as 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2(NO)]. This conversion was accompanied by a decrease of the mutagenicity of the mixture, as monitored by the direct-acting mutagenicity on Salmonella typhimurium TA98; a rapid change to approximately 1/3 of the original mutagenicity was followed by no further decrease of the activity. In contrast, in the spontaneous aerobic oxidation of Trp-P-2-(NHOH), the mutagenicity slowly and continuously decreased, until it was finally lost almost completely. Similar acceleration by SOD of aerobic oxidation was found for 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [Glu-P-1(NHOH)]. Again, mutagenicity of approximately 1/4 that of the original was retained in the SOD-mediated decomposition, while a complete loss of the mutagenicity was observed in the spontaneous decomposition. When Trp-P-2(NO) was treated with the superoxide-generating system, xanthine oxidase plus xanthine, Trp-P-2(NHOH) was formed. Therefore, the role of SOD in the conversion of Trp-P-2(NHOH) into Trp-P-2(NO) is the removal of superoxide anions generated by reduction of aerobic oxygen, thereby inhibiting the reverse reactions, i.e. the reduction of Trp-P-2(NO) and that of the putative intermediate nitroxide radical. In support of this proposed mechanism, phenylhydroxylamine underwent a SOD-accelerated conversion to nitrosobenzene, and nitrosobenzene was reduced to phenylhydroxylamine by the action of the xanthine oxidase-xanthine system. Hence, this reversible interchange between an arylhydroxylamine and its nitroso compound, coupled with the oxygen-superoxide cycle, may be a general phenomenon. A consequence of this finding is that the xenobiotic N-hydroxylamines may be converted by the action of SOD in the biological settings into nitroso compounds, which are chemically more stable, serving as a reservoir for mutagenicity.
authors.affiliation: Faculty of Pharmaceutical Sciences, Okayama University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hiramoto
authors.forename: K
authors.initials: K
authors.lastname: Negishi
authors.forename: T
authors.initials: T
authors.lastname: Namba
authors.forename: T
authors.initials: T
authors.lastname: Katsu
authors.forename: H
authors.initials: H
authors.lastname: Hayatsu
mesh_terms: D002243:Carbolines / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D006861:Hydrogen Peroxide; D006898:Hydroxylamines; D007093:Imidazoles / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009603:Nitroso Compounds; D010084:Oxidation-Reduction; D011506:Proteins; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D002243:Carbolines; D006898:Hydroxylamines; D007093:Imidazoles; D009153:Mutagens; D009603:Nitroso Compounds; D011506:Proteins; D013481:Superoxides; C012484:phenylhydroxylamine; C023786:2-hydroxyamino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C027210:3-hydroxyamino-1-methyl-5H-pyrido(4,3-b)indole; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase