HRP-catalyzed bioactivation of carcinogenic hydroxamic acids. The greater reactivity of glycolyl- versus acetyl-derived hydroxamic acids.
An analysis of the hydroxamic acid oxidation reaction by H2O2 and horseradish peroxidase (HRP) was made with three pairs of hydroxamic acids. Each pair consisted of the aceto- and glycolhydroxamic acid derivatives from one of three different arylhydroxylamines. The parent arylhydroxylamines were the known carcinogens, N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl and the noncarcinogen 4-chlorophenyl-hydroxylamine. All the hydroxamic acids appeared to be converted to products that were expected on the basis of the previously-proposed mechanism of this peroxidative reaction. Each acetohydroxamic acid gave the corresponding nitroso compound and O-acetyl ester of the starting material in approximately equal amounts. The glycolhydroxamic acids gave the corresponding nitroso compound and a relatively unstable product that was proposed, by analogy, to be the O-glycolyl ester of the starting material. A comparison of the initial rates of reaction of each hydroxamic acid pair showed that the glycolhydroxamic acid was much more susceptible to the peroxidation reaction than was the corresponding acetohydroxamic acid. The initial rate of the reaction was also highly dependent upon the nature of the aromatic ring in the order fluorene greater than biphenyl greater than 4-chlorophenyl. The relative degree of HRP-catalyzed covalent binding to DNA of the aceto- and glycolhydroxamic acids in the fluorene series was studied and found to parallel the relative rates of reaction of these substrates in the H2O2/HRP system. It was proposed that glycolhydroxamic acids are likely to be more genotoxic than are acetohydroxamic acids when subjected to peroxidative bioactivation conditions.
Corbett
M D
MD
Department of Food Science and Human Nutrition, University of Florida, Gainesville 32611.
Corbett
B R
BR
D001711:Biotransformation; D002273:Carcinogens; D004249:DNA Damage; D006735:Horseradish Peroxidase; D006860:Hydrogen Bonding; D006861:Hydrogen Peroxide; D006877:Hydroxamic Acids; D006881:Hydroxyacetylaminofluorene / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D007700:Kinetics; D009153:Mutagens; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D002273:Carcinogens; D006877:Hydroxamic Acids; D009153:Mutagens; C054220:N-hydroxy-2-glycolylaminofluorene; D006881:Hydroxyacetylaminofluorene; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase