Metabolism of diethylnitrosamine by nasal mucosa and hepatic microsomes from hamster and rat: species specificity of nasal mucosa.
The oxidative metabolism of diethylnitrosamine (DEN) was investigated by acetaldehyde determination using microsomes from nasal mucosa and liver of Sprague-Dawley rats and nasal mucosa and liver of Syrian Golden hamsters, to establish the role of metabolic activation in the organo-targets for the carcinogenicity of the nitrosamine. The hepatic microsomal de-ethylation of DEN followed simple and biphasic Michaelis-Menten kinetics for rat liver and hamster liver, respectively. Both de-ethylations were inducible by phenobarbital (PB) and the DEN-de-ethylase activities and the Michaelis constants were determined. Microsomes from hamster liver showed a higher metabolic rate (Vmax) and a better affinity (Km) towards DEN with respect to microsomes from rat liver. In hamster, microsomes from nasal tissue biotransformed DEN at a rate and affinity quite similar to those of liver. In contrast, nasal mucosa of rat metabolized DEN poorly. The effect of metyrapone, a classical inhibitor of P-450 monooxygenases, on DEN de-ethylation was studied. It inhibited both hepatic and nasal DEN-de-ethylase activity, with greater affinity towards the latter. In addition metyrapone had a greater inhibitory effect on the hepatic P-450 isozymes induced in PB-treated animals. These results correlate well with the organotrophy of DEN carcinogenesis in the nasal region of hamster, but not of rat. They suggest that for the nose the metabolic activation of DEN in situ is necessary to elicit its carcinogenic effect.
D000818:Animals; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003640:Dealkylation; D004052:Diethylnitrosamine / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism*; D009297:Nasal Mucosa / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002245:Carbon Dioxide; D004052:Diethylnitrosamine; D003577:Cytochrome P-450 Enzyme System