Neuroendocrinology Letters 2010-01-01

Identification of rat cytochromes P450 metabolizing N-(2-methoxyphenyl)hydroxylamine, a human metabolite of the environmental pollutants and carcinogens o-anisidine and o-nitroanisole.

Karel Naiman, Eva Frei, Marie Stiborova

Index: Neuro Endocrinol. Lett. 31 Suppl 2 , 36-45, (2010)

Full Text: HTML

Abstract

N-(2-methoxyphenyl)hydroxylamine is a human metabolite of two industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole). Metabolism of N-(2-methoxyphenyl)hydroxylamine by rat hepatic microsomes and identification of the major microsomal enzymes participating in this process are aims of this study.HPLC with UV detection was employed for the separation of N-(2-methoxyphenyl)hydroxylamine metabolites. Inducers and inhibitors of microsomal enzymes and rat recombinant CYPs were used to characterize the enzymes participating in N-(2-methoxyphenyl)hydroxylamine metabolism.N-(2-methoxyphenyl)hydroxylamine is metabolized by rat hepatic microsomes predominantly to o-anisidine, the parent carcinogen from which N-(2-methoxyphenyl)hydroxylamine is formed, while o-aminophenol and two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, are minor products. Selective inhibitors of microsomal CYPs, NADPH:CYP reductase and NADH:cytochrome b5 reductase and hepatic microsomes of rats pre-treated with specific inducers of CYPs and NADPH:CYP reductase were used to characterize rat liver microsomal enzymes reducing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. Based on these studies, we attribute most of N-(2-methoxyphenyl)hydroxylamine metabolism to o-anisidine in rat liver to CYP2C, followed by CYP2E1, 2D and 2A. Among recombinant rat CYP enzymes tested in this study, rat CYP2C11 and 2E1, followed by CYP2A2, 2D1/2, 2C12, 3A1/2 and 1A1/2 were the most efficient enzymes metabolizing N-(2-methoxyphenyl)hydroxylamine to o-anisidine.The results found in this study, the first report on the reduction of N-(2-methoxyphenyl)hydroxylamine by rat CYP enzymes, demonstrate that CYP2C, followed by CYP2E1, 2D and 2A are the major enzymes participating in this process in rat liver.

Related Compounds

  • 2-Anisidine
  • nitroanisole

Related Articles:

Toxicological assessment of kretek cigarettes: Part 1: background, assessment approach, and summary of findings.

2014-12-01

[Regul Toxicol Pharmacol 70 Suppl 1 , S2-14, (2014)]

Monoarylamines in the general population--a cross-sectional population-based study including 1004 Bavarian subjects.

2009-05-01

[Int. J. Hyg. Environ. Health 212(3) , 298-309, (2009)]

Redox cycling in the metabolism of the environmental pollutant and suspected human carcinogen o-anisidine by rat and rabbit hepatic microsomes.

2008-08-01

[Chem. Res. Toxicol. 21(8) , 1610-21, (2008)]

Identification of a genotoxic mechanism for the carcinogenicity of the environmental pollutant and suspected human carcinogen o-anisidine.

2005-09-20

[Int. J. Cancer 116(5) , 667-78, (2005)]

Dynamic scale theory for characterizing surface morphology of layer-by-layer films of poly(o-methoxyaniline).

2004-05-01

[J. Nanosci. Nanotechnol. 4(5) , 548-52, (2004)]

More Articles...