<abstract xml:lang="en" xmlns="http://www.w3.org/1999/xhtml"><p><italic>N</italic>-(2-methoxyphenyl)hydroxylamine is a human metabolite of the industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (<italic>o</italic>-anisidine) and 2-methoxynitrobenzene (<italic>o</italic>-nitroanisole). Here, we investigated the ability of hepatic microsomes from rat and rabbit to metabolize this reactive compound. We found that <italic>N</italic>-(2-methoxyphenyl)hydroxylamine is metabolized by microsomes of both species mainly to <italic>o</italic>-aminophenol and a parent carcinogen, <italic>o</italic>-anisidine, whereas 2-methoxynitrosobenzene (<italic>o</italic>-nitrosoanisole) is formed as a minor metabolite. Another <italic>N</italic>-(2-methoxyphenyl)hydroxylamine metabolite, the exact structure of which has not been identified as yet, was generated by hepatic microsomes of rabbits, but its formation by those of rats was negligible. To evaluate the role of rat hepatic microsomal cytochromes P450 (CYP) in <italic>N</italic>-(2-methoxyphenyl)hydroxylamine metabolism, we investigated the modulation of its metabolism by specific inducers of these enzymes. The results of this study show that rat hepatic CYPs of a 1A subfamily and, to a lesser extent those of a 2B subfamily, catalyze <italic>N</italic>-(2-methoxyphenyl)hydroxylamine conversion to form both its reductive metabolite, <italic>o</italic>-anisidine, and <italic>o</italic>-aminophenol. CYP2E1 is the most efficient enzyme catalyzing conversion of <italic>N</italic>-(2-methoxyphenyl)hydroxylamine to <italic>o</italic>-aminophenol.</p></abstract>

N-(2-methoxyphenyl)hydroxylamine is a human metabolite of the industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole). Here, we investigated the ability of hepatic microsomes from rat and rabbit to metabolize this reactive compound. We found that N-(2-methoxyphenyl)hydroxylamine is metabolized by microsomes of both species mainly to o-aminophenol and a parent carcinogen, o-anisidine, whereas 2-methoxynitrosobenzene (o-nitrosoanisole) is formed as a minor metabolite. Another N-(2-methoxyphenyl)hydroxylamine metabolite, the exact structure of which has not been identified as yet, was generated by hepatic microsomes of rabbits, but its formation by those of rats was negligible. To evaluate the role of rat hepatic microsomal cytochromes P450 (CYP) in N-(2-methoxyphenyl)hydroxylamine metabolism, we investigated the modulation of its metabolism by specific inducers of these enzymes. The results of this study show that rat hepatic CYPs of a 1A subfamily and, to a lesser extent those of a 2B subfamily, catalyze N-(2-methoxyphenyl)hydroxylamine conversion to form both its reductive metabolite, o-anisidine, and o-aminophenol. CYP2E1 is the most efficient enzyme catalyzing conversion of N-(2-methoxyphenyl)hydroxylamine to o-aminophenol.

Cytochrome P450-mediated metabolism of <italic>N</italic>-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens <italic>o</italic>-anisidine and <italic>o</italic>-nitroanisole

Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic

Institut of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences, Prague, Czech Republic

Department of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic

Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany

Interdisciplinary Toxicology

Cytochrome P450-mediated metabolism of -(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens -anisidine and -nitroanisole

N-(2-methoxyphenyl)hydroxylamine is a human metabolite of the industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine)...

Cytochrome P450-mediated metabolism of N-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens o-anisidine and o-nitroanisole

Published Online: Nov 01, 2010

Page range: 218 - 224

DOI: https://doi.org/10.2478/v10102-010-0045-8

Keywords
-anisidine, -(2-methoxyphenyl)hydroxylamine, metabolism, oxidation, cytochrome P450

This content is open access.