Abstract

Hepatic microsomal cytochrome P-450 from phenobarbital-pretreated rats is destroyed in vitro, in the presence of NADPH, by terminal (monosubstituted) olefins such as 4-ethyl-1-hexene and 1-heptene. The destructive interaction apparently depends on no other factor than the presence of a carbon-carbon double bond, since ethylene gas is an effective destructive agent. Hepatic "green" pigments are formed on the administration of terminal olefins to phenobarbital-pretreated rats. These pigments are essentially identical, by electronic absorption spectroscopy, to that previously reported to be formed on the administration of 2-isopropyl-4-pentenamide. Although cis- and trans-2-nonene exhibit marginal destructive activity, no abnormal pigments were found after in vivo administration. No cytochrome P-450 loss is observed after incubation with styrene, cyclohexene, 2-methyl-1-heptene, and 3-hexene, a result which suggests that steric and electronic factors can suppress the destructive interaction. The epoxides of three of the terminal olefin substrates have been synthesized and shown not to intervene in destruction of the enzyme by the parent olefins. Mechanistic and physiological implications of these observations are discussed.