SPECIES AND SEX DIFFERENCES IN THE SUBSTRATE-INDUCED SPECTRAL CHANGE OF P-450 IN RELATION TO THE ACTIVITY OF DRUG OXIDATION IN LIVER MICROSOMES

Abstract

A number of foreign compounds of high lipid-solubility are oxidatively metabolized to more water soluble compounds by liver microsomal hydroxylase system, called drugmetabolizing enzymes, in the presence of NADPH and oxygen (1, 2). There are marked species differences among various animals in the activity of drugmetabolizing enzymes, and these species differences are assumed to be responsible factors for the species differences in the effect and toxicity of a variety of drugs (2-5). Recent studies have established that a hemoprotein called P-450 (6) is involved in the monooxygenase reactions in liver microsomes as the oxygen-activating component (7-9). More recently, Imai and Sato (10), and Schenkman et al. (11) have reported that a number of drugs, substrates of hepatic microsomal monooxygenases, react with the microsomal cytochrome to give two characteristic types of spectral change. These results have suggested that the spectral changes observed are indicative of substrate interaction for enzymic hydroxylation (11) and that the magnitude of the substrate binding with cytochrome P-450 is one of important factors for the rate of the over-all hydroxylation of drugs by liver microsomes. It was therefore of interest to investigate whether the magnitude of the substrate binding with P-450 is related to the activity of hydroxylations of drugs by liver microsomes of various species of animals. In the present communication, the magnitude of the substrate binding with P-450 has been investigated in both sexes of rats, mice and rabbits.