Effect of Dietary Protein Deficiency on Rat Hepatic Drug-Metabolizing Enzyme System

Abstract

Abstract-Wehave examined the effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system for a period of two months. Cytochrome P-450 and b5 contents in liver microsomes, which were plotted on semilogarithmic paper as a function of the time of deficiency, showed biphasical reductions during protein deficiency: rapid decreases in the first 3 weeks were followed by more gradual decreases. However, the three enzymatic activities examined, i.e. aminopyrine demethylase, aniline hydroxylase and p-nitroanisole demethylase, were not reduced at a uniform rate. In the earlier phase, activities of the former two enzymes were reduced more rapidly than that of the last phase. This biphasical and non-uniform reduction of enzymatic activities suggests the existence of two or more cytochrome P-450 subspecies in nondepleted male rats. Intraperitoneal administration of well-known environmental pollutants, polychlorinated dibenzofurans and biphenyls (100 fig and 100 mg/kg, respectively) to the depleted rats resulted in a marked induction of drug-metabolizing enzymes. However, as the deficiency became more severe (2 months), the induction declined to a considerable degree, especially in the case of polychlorinated biphenyl administration.In 1952, V.A. Drill presented a review concerning the interaction between hepatotoxins and dietary factors, in which he showed that protein deficiency affected the toxicity of the various hepatotoxins (1). Since then, many laboratories have shown that protein deficiency decreases the microsomal oxidation rates of a great variety of drugs and other foreign chemicals (2-4). Boyd and his colleagues (5, 6) observed that many pesticides indicated increased toxicity in protein-depleted animals, as illustrated by a 2,100-fold increase in the toxicity of captan (5). In contrast, some compounds such as carbon tetrachloride (7) and heptachlor (8) have shown lower toxicities. These increased or decreased toxicities observed in protein-depleted animals are generally interpreted to be caused by the depression of foreign chemical metabolism during protein deficiency.In the last decade, several investigators suggested that different forms of cytochrome P-450 existed in liver microsomes, and their arguments were actually proved by the purification of several cy tochrome P-450 and P-448 subspecies different in spectral properties, minimal molecular weight, substrate specificities or immunological properties (9).In the present report we have examined the time course of the decrease of rat hepatic hemoprotein contents and drug-oxidation activities during protein deficiency, and obtained results suggesting that different cytochrome P-450 subspecies were reduced at very different rates. We have also examined the induction of these enzymes caused by polychlorinated

Effects of pregnancy and protein-energy malnutrition on monooxygenase O-dealkylation activity in rat liver microsomes

“…Low-protein diets and protein-energy malnutrition (e.g., restricted feeding, starvation) have generally been found to decrease both phase I oxidative metabolism and phase II conjugation reactions in nonpregnant animals (8,10,11). Our data suggest that, at least as far as EROD and PROD are concerned, protein-energy malnutrition does not increase the reduction of enzyme activity caused by pregnancy itself.…”

“…The effects of malnutrition (e.g., low protein diets, fasting or restricted feeding) on the metabolism of xenobiotics have been investigated in male and nonpregnant female rats by several research groups (8)(9)(10)(11). Despite the marked differences in experimental design, these studies have generally found that protein deficiency and proteinenergy malnutrition (i.e., restricted feeding) cause a depression of hepatic monooxygenase activities, thereby slowing the rate of xenobiotic biotransformation (8,10,11).…”

“…Despite the marked differences in experimental design, these studies have generally found that protein deficiency and proteinenergy malnutrition (i.e., restricted feeding) cause a depression of hepatic monooxygenase activities, thereby slowing the rate of xenobiotic biotransformation (8,10,11).…”

Restriction protéique et métabolisme des xénobiotiques

“…De même pour l'aminopyrine déméthy lase. Kawano et Hiraya [17] notent aussi une moindre induction par le Kaneclor 500 chez le rat Wistar. Cela pourrait être lié à un apport insuffisant en méthionine et cystéine.…”

Species and strain differences in the butylated hydroxytoluene (BHT)-producing induction of hepatic drug oxidation enzymes.

“…Chemicals: Materials and their sources are as follows: butylated hydroxytoluene (BHT) and a-naphthoflavone (7,8- and DBA/2N (14-18 g) were purchased from Charles River Japan Inc. The environment of the animal room was rigidly controlled, as previously described (11). The rats were housed in stainless steel wire cages, and the mice on cedar bedding in aluminium cages.…”