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The mutagenic mechanism of oxygenated alkylhydrazones occurs through alkyl radicals and alkyldiazonium ions.

ABSTRACT: Acetone alkylhydrazones have been reported to be mutagenic in Salmonella typhimurium TA1535 after exposure to oxygen, and the corresponding 2-alkylazo-2-propyl hydroperoxides are formed by autoxidation as a result. The aims of this study were to investigate the mutagenic mechanisms of a methyl analogue, 2-methylazo-2-propyl hydroperoxide (MAPH), by comparing the mutagenic potency of specific Salmonella strains, detecting the DNA adducts that cause mutagenicity, and observing the hydroxyl radical and methyl radical with the electron spin resonance (ESR) spin-trapping method. MAPH showed stronger mutagenicity in both Salmonella typhimurium YG3001, a strain sensitive to hydroxyl radicals, and Salmonella typhimurium YG7108, a strain sensitive to alkylating agents, than the original Salmonella typhimurium TA1535 strain. Moreover, MAPH resulted in the formation of 8-hydroxy-2'-deoxyguanosine and O⁶-methyl-2'-deoxyguanosine in a reaction with DNA. These results showed that the mutagenicity of hydrazones was ascribed to the generation of reactive species by autoxidation, namely that of the alkyldiazonium ion and also the hydroxyl radical.

SUBMITTER: Inami K

PROVIDER: S-EPMC6062409 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The mutagenic mechanism of oxygenated alkylhydrazones occurs through alkyl radicals and alkyldiazonium ions.

Inami Keiko K Takada Miki M Nagata Miho M Higashi Toshinori T Mochizuki Masataka M

Toxicology research 20170202 2

Acetone alkylhydrazones have been reported to be mutagenic in <i>Salmonella typhimurium</i> TA1535 after exposure to oxygen, and the corresponding 2-alkylazo-2-propyl hydroperoxides are formed by autoxidation as a result. The aims of this study were to investigate the mutagenic mechanisms of a methyl analogue, 2-methylazo-2-propyl hydroperoxide (MAPH), by comparing the mutagenic potency of specific <i>Salmonella</i> strains, detecting the DNA adducts that cause mutagenicity, and observing the hy ...[more]

PMID: 30090487

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Project description:Polychlorinated biphenyls (PCBs) can be oxygenated to form very reactive hydroquinone and quinone products. A guiding hypothesis in the PCB research community is that some of the detrimental health effects of some PCBs are a consequence of these oxygenated forms undergoing one-electron oxidation or reduction, generating semiquinone radicals (SQ (*-)). These radicals can enter into a futile redox cycle resulting in the formation of reactive oxygen species, that is, superoxide and hydrogen peroxide. Here, we examine some of the properties and chemistry of these semiquinone free radicals. Using electron paramagnetic resonance (EPR) to detect SQ (*-) formation, we observed that (i) xanthine oxidase can reduce quinone PCBs to the corresponding SQ (*-); (ii) the heme-containing peroxidases (horseradish and lactoperoxidase) can oxidize hydroquinone PCBs to the corresponding SQ (*-); (iii) tyrosinase acting on PCB ortho-hydroquinones leads to the formation of SQ (*-); (iv) mixtures of PCB quinone and hydroquinone form SQ (*-) via a comproportionation reaction; (v) SQ (*-) are formed when hydroquinone-PCBs undergo autoxidation in high pH buffer (approximately >pH 8); and, surprisingly, (vi) quinone-PCBs in high pH buffer can also form SQ (*-); (vii) these observations along with EPR suggest that hydroxide anion can add to the quinone ring; (viii) H 2 O 2 in basic solution reacts rapidly with PCB-quinones; and (ix) at near-neutral pH SOD can catalyze the oxidization of PCB-hydroquinone to quinone, yielding H 2 O 2. However, using 5,5-dimethylpyrroline-1-oxide (DMPO) as a spin-trapping agent, we did not trap superoxide, indicating that generation of superoxide from SQ (*-) is not kinetically favorable. These observations demonstrate multiple routes for the formation of SQ (*-) from PCB-quinones and hydroquinones. Our data also point to futile redox cycling as being one mechanism by which oxygenated PCBs can lead to the formation of reactive oxygen species, but this is most efficient in the presence of SOD.

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The mutagenic mechanism of oxygenated alkylhydrazones occurs through alkyl radicals and alkyldiazonium ions.

Publications

The mutagenic mechanism of oxygenated alkylhydrazones occurs through alkyl radicals and alkyldiazonium ions.

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