nitrophenols and 2-nitroanisole

2-Nitrophenol (2-NP) is the major detoxification metabolite of an important industrial pollutant and a potent carcinogen, 2-nitroanisole (2-NA). Characterization of the products of 2-NP metabolism by rat hepatic microsomes containing cytochromes P450 (CYPs) and identification of the major CYP enzymes participating in this process are aims of this study.. HPLC with UV detection was employed for the separation and characterization of 2-NP metabolites. Inducers and inhibitors of CYPs and rat recombinant CYPs were used to characterize the enzymes participating in 2-NP oxidation.. Rat hepatic microsomes oxidize 2-NP to its hydroxylated metabolite, 2,5-dihydroxynitrobenzene (2,5-DNB). No nitroreductive metabolism leading to the formation of o-aminophenol was evident when using rat hepatic microsomes. Selective CYP inhibitors and hepatic microsomes of rats pre-treated with specific CYP inducers were used to characterize CYPs oxidizing 2-NP in rat livers. Based on these studies, we attribute most of 2-NP oxidation in rat liver to CYP2E1 and 3A, followed by CYP2D and 2C. Among recombinant rat CYP enzymes tested in this study, CYP2E1 and 2C11 were the most effective enzymes oxidizing 2-NP. Oxidation of 2-NP by rat CYP2E1 exhibits the Michaelis-Menten kinetics, having the Km value of 0.35 mM.. The results found in this study, the first report on the metabolism of 2-NP by rat hepatic microsomes and rat CYP enzymes, demonstrate that CYP2E1 is the major enzyme oxidizing this compound in rat liver.

Topics: Animals; Anisoles; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Inhibitory Concentration 50; Kinetics; Microsomes, Liver; Nitrophenols; Oxidation-Reduction; Rats; Recombinant Proteins; Ultraviolet Rays

A major chemical accident occurred on 22 February 1993 at plant Griesheim of Hoechst AG Frankfurt/Germany during which approximately 11.8 tons of a chemical mixture containing mostly chlorinated nitroarenes were emitted leading to serious contaminations in Schwanheim/Goldheim, a nearby housing area. Numerous inhabitants of the contaminated area complained of irritation of eyes, skin and mucous membranes, headache and nausea, and 92 persons with moderate symptoms were reported to the National Health Department. Urine samples were collected from the inhabitants of the affected area a few days after the accident and analysed for o-nitrophenol as a representative metabolite to assess the actual uptake of pollutants. O-nitrophenol, however, was also detected in the urine of not knowingly exposed control subjects, an observation not hitherto described in literature. The median levels of o-nitrophenol were three times higher in the exposed population than in the controls. Taking into account the data on pollution measured in the environment, the reported intoxication symptoms, the results of biomonitoring, and the published literature on the components of the mixture, the following conclusions were drawn: (1) The exposure was not high enough to cause severe acute toxic effects. (2) Although the emitted mixture contained carcinogenic components according to animal experiments, the transient exposure to these chemicals does not increase the tumour risk to any measurable extent, i.e. demonstrable by epidemiological methods, especially if weighed against the permanent exposure to "normal" urban pollution.

Topics: Accidents, Occupational; Adult; Air Pollutants, Occupational; Animals; Anisoles; Chemical Industry; Child; Environmental Exposure; Environmental Monitoring; Germany; Humans; Maximum Allowable Concentration; Mice; Nitrobenzenes; Nitrophenols; Rats

Topics: Animal Feed; Animals; Anisoles; Biological Availability; Creatinine; Food, Formulated; Male; Nitrophenols; Rats; Rats, Inbred F344; Time Factors