Oxidative detoxication of carcinogenic 2-nitroanisole by human, rat and rabbit cytochrome P450
Language English Country Sweden Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
17159769
PII: NEL270806A01
Knihovny.cz E-resources
- MeSH
- Aniline Compounds metabolism MeSH
- Anisoles pharmacokinetics MeSH
- Child MeSH
- Adult MeSH
- Metabolic Detoxication, Phase I * MeSH
- Microsomes, Liver metabolism MeSH
- Carcinogens pharmacokinetics MeSH
- Rabbits MeSH
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- NAD(P)H Dehydrogenase (Quinone) metabolism MeSH
- Rats, Wistar MeSH
- Child, Preschool MeSH
- Aged MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Rabbits MeSH
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-anisidine MeSH Browser
- 2-nitroanisole MeSH Browser
- Aniline Compounds MeSH
- Anisoles MeSH
- Carcinogens MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- NQO1 protein, human MeSH Browser
- Cytochrome P-450 Enzyme System MeSH
OBJECTIVES: The detoxifying metabolism of a potent rodent carcinogen, 2-nitroanisole (2-NA) by human, rabbit and rat cytochromes P450 (P450) was investigated. Comparison between P450s of experimental animals and humans is essential for the extrapolation of animal carcinogenicity data to the human situation and to assess health risk. METHODS: HPLC with UV detection was employed for the separation and characterization of 2-NA metabolites formed by hepatic microsomes, human recombinant P450s and purified rat and rabbit P450s. RESULTS: An O-demethylated metabolite of 2-NA, 2-nitrophenol (2-NP), and two oxidation products of this metabolite [2,5-dihydroxynitrobenzene (2,5-DNB) and 2,6-dihydroxynitrobenzene (2,6-DNB)] were generated by microsomes and P450s from the species investigated, but at different levels. All the metabolites are detoxication products. 2-NP is the major metabolite generated by rabbit and rat microsomes, but 2,5-DNB is the predominant product in human microsomes. Using human recombinant P450s and purified rodent P450s, we found that human P450 2E1, 1A1 and 2B6 as well as orthologous animal P450s were the most efficient enzymes oxidizing 2-NA to 2-NP, while P450 2E1 and 1A1 were the most effective in the formation of 2,5-DNB and 2,6-DNB. In human hepatic microsomes, 2-NA was oxidized mainly by P4502E1. 2-NA and its reductive metabolite o-anisidine induced rat hepatic and renal P450 1A1/2 and NAD(P)H:quinone oxidoreductase (NQO1), thus modifying their own detoxication and/or activation pathways. CONCLUSIONS: The data demonstrated the participation of orthologous P450s in 2-NA oxidation by all species and indicated that the rat and rabbit might serve as suitable models to mimic 2-NA oxidation in man.
