Cytochrome P-450 Mixed Function Oxidase Research Articles

Enzymatic oxidation of diphenylmethylphosphine and 3-dimethylaminopropyldiphenylphosphine by rat liver microsomes

The metabolism of two tertiary aromatic phosphines, 3-dimethylaminopropyldiphenylphosphine (a CNS depressant) and diphenylmethylphosphine, was studied. These compounds were incubated with subcellular fractions of rat liver homogenates and found to be enzymatically converted to the corresponding phosphine oxides; the aminophosphine gave rise to an N, P-dioxide. Enzymatic activity was localized in the microsomal fraction and shown to be associated with the cytochrome P-450 mixed function oxidases. The substrates were also found to undergo a facile non-enzymatic reaction with thiols, a factor which portends their possible chronic toxicity.

Effects of chlordane and methylmercury on the metabolism of carbaryl and carbofuran in rats

Methylmercury hydroxide pretreatments (10 mg/kg/day for 2 days) decreased hepatic microsomal cytochrome P-450 levels and mixed function oxidase activity over twofold, while chlordane pretreatments (20 mg/kg/day for 2 days) induced the oxidative enzymes nearly twofold. Methylmercury hydroxide pretreatments also decreased microsomal hydroxylation reactions of carbaryl and carbofuran to form 4-hydroxy carbaryl, N-hydroxymethyl carbaryl and 3-hydroxy carbofuran. Chlordane pretreatments increased hydroxylation rates at these positions and also increased the amount of carbamate- 14C equivalents detected in the water-extractable fraction. When chlordane and methylmercury hydroxide were administered simultaneously the effects balanced out so that carbamate metabolism using microsomes from this group was similar to controls. In whole animal metabolism studies, chlordane pretreatment increased the rate of urinary elimination of carbaryl and carbofuran equivalents. Methylmercury hydroxide, unexpectedly, also increased urinary excretion of both carbamate equivalents and possible mechanisms involved in the enhancement of urinary excretion are investigated. Chlordane and methylmercury hydroxide pretreatment did not qualitatively alter microsomal or urinary carbamate metabolites, although some quantitative differences were observed.