EFFECT OF VITAMIN C DEFICIENCY ON THE METABOLISM OF DRUGS AND NADPH-LINKED ELECTRON TRANSPORT SYSTEM IN LIVER MICROSOMES

Abstract

Various drugs are inactivated by liver microsomes in the presence of NADPH and atomospheric oxygen (1). The enzymes catalyzing these reactions can activate molecular oxygen by a 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 (1, 2). Recently the participation in these reactions of hemoprotein called cytochrome P-450 (3) as the oxygen-activating component (4-8) has been established (Fig. 1). The activity of drug-metabolizing enzymes of liver microsomes was altered by various factors, such as the administration of phenobarbital or methylcholanthrene (9, 10), thyroxine (11-13), anabolic hormone (11, 14, 15), carbon tetrachloride (11, 16) and morphine (11, 12), and adrenalectomy (11, 17), thyroidectomy (13), hepatectomy (18), starvation (19, 20), alloxan diabetes (11, 12) and low protein diet (16, 21, 22). It was also demonstrated that the activity of NADPH-linked electron transport system of liver microsomes was often altered in association with the alteration in the activity of drug-metabolizing enzymes under the above-given conditions (10, 13, 22, 26). Vitamin C is a well known component related to the control of oxido-reduction states of living cell, but detailed role of vitamin C has not been fully elucidated (27). On the other hand, Mitoma et al. (28), Tochino et al. (29) and more recently, Conney et al. (30) reported that the hydroxylation of acetanilide, hexobarbital and zoxazolamine was decreased in vitamin C deficient guinea-pigs. However, the studies on the mechanism of decreased hydroxylation activity in relation to the activity of NADPH-linked electron transport system has not yet been reported. The purpose of the present study, therefore, is to investigate whether or not the mechanism of decreased hydroxylation activity of liver microsomes from vitamin C deficient guinea-pigs is related to the decreased activity of NADPH-linked electron transport system.