DIFFERENCES IN THE OXIDATIVE METABOLISM OF DRUGS BY LIVER MICROSOMES

Abstract

Various foreign compounds were oxidized in liver microsomes by so-called “microsomal drug-metabolizing enzymes” under the presence of NADPH and atmospheric oxygen (1). The enzymes catalyzing these reactions can activate molecular oxygen by two-electron reduction so that one oxygen atom is introduced into the substrate leading to a hydroxylated product, whereas the second atom is reduced to water. Since microsomal cytochrome P-450 is involved in the oxidation of drugs, the following tentative pathway has been postulated (2-4) (Fig. 1). It is well known that one of the characteristic of these enzyme systems is a low substrate specificity and indeed highly lipid-soluble compounds were metabolized by these enzyme systems (1). These reactions including hydroxylation of alkyl side-chain, hydroxylation of aromatic and non-aromatic rings, N-dealkylation, O-dealkylation, sulfoxidation and N-oxidation. However, it is not yet determined whether or not cytochrome P-450 acts as only an oxygen-activated component and the terminal oxidase is required for the oxidation of drugs. In other words, it is not clear whether or not activated oxygen of cytochrome P-450 is transfered non-enzymatically into drug molecule. In the present communication, we wish to report the evidence which may suggest the presence of the terminal oxidase and moreover the presence of more than two kinds of hydroxylase and N-demethylase. The results indicate that the terminal oxidase which hydroxylates pentobarbital and hexobarbital is likely differ from that which hydroxylates aniline and zoxazolamine for the following reasons: the presence of marked sex difference in the activity, the difference in the effect of methylcholanthrene and some inhibitors, such as SKF 525A and DPEA and the difference in the enzyme stability (1, 6, 7). Similarly, the terminal oxidase which N-demethylates aminopyrine is likely differ from that N-demethylates N-methylaniline.