Metabolism of [(1)(4)C]prometryn in rats.

[(1)(4)C]Prometryn, 2, 4-bis(isopropylamino)-6-(methylthio)-s-triazine, was orally administered to male and female rats at approximately 0.5 and 500 mg/kg; daily urine and feces were collected. After 3 or 7 days rats were sacrificed, and blood and selected tissues were isolated. The urine and feces extracts were characterized for metabolite similarity as well as for metabolite identification. Over 30 metabolites were observed, and of these, 28 were identified mostly by mass spectrometry and/or cochromatography with available reference standards. The metabolism of prometryn was shown to occur by N-demethylation, S-oxidation, S-S dimerization, OH substitution for NH(2) and SCH(3), and conjugation with glutathione or glucuronic acid. Rat liver microsomal incubations of prometryn were conducted and compared to the in vivo metabolism. Both in vivo and in vitro phase I metabolisms of prometryn were similar, with S-oxidation and N-dealkylation predominating. The involvement of cytochrome P-450 and flavin-containing monooxidase in the in vitro metabolism of prometryn was investigated.

The opposing effects of N-hydroxyamphetamine and N-hydroxyphentermine on the H2O2 generated by hepatic cytochrome P-450.

The effects of N-hydroxyphentermine (NOHP) and N-hydroxyamphetamine (NOHA) on hydrogen peroxide generated by rat liver microsomes and reconstituted preparations in the presence of NADPH were compared. In microsome incubations, NOHP caused an increase in H2O2 levels and NOHA caused a substantial decrease. When the substances were compared for cytochrome P-450-dependent H2O2 generation in reconstituted preparations, NOHA at mM blocked generation and NOHP had no effect. NOHP appears to be an uncoupler of the cytochrome P-450 system in microsomes whereas NOHA is a potent inhibitor, presumably because of its ability to form a metabolic intermediate complex. During the course of their effects on O2 reduction, NOHP and NOHA are themselves undergoing oxidation, NOHP to 2-methyl-2-nitro-1-phenylpropane and NOHA to phenylacetone oxime. The enzymatic natures of these oxidations differ. Thus, two closely related arylalkylhydroxylamines differ substantially in their interaction with cytochrome P-450 systems.