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Ascorbic Acid Requirement for the Induction of Microsomal Drug-Metabolizing Enzymes in a Rat Mutant Unable to Synthesize Ascorbic Acid¹

Department of Agricultural Chemistry, Nagoya University, Nagoya 464 Japan ^* Aburahi Laboratories, Shionogi Research Laboratories, Shionogi & Co., Ltd., Gotanda, Koga-gun, Shiga 520-34, Japan

We investigated the requirement of ascorbic acid for the induction by polychlorinated biphenyls (PCB) of hepatic drug-metabolizing enzymes in ODS-od/od rat (OD rat) which is a rat mutant unable to synthesize ascorbic acid. ODS- + / + rats (+ / + rat), which can synthesize ascorbic acid, were used as controls. In OD rats, the dietary requirement of ascorbic acid to maintain normal growth and prevent any signs of scurvy is about 300 mg of ascorbic acid per kilogram diet. In this study, dietary levels of ascorbic acid tested were 0, 50, 300, 1000 and 3000 mg ascorbic acid per kilogram diet with or without 200 mg of PCB per kilogram diet. Feeding PCB did not affect growth in rats of either genotype. When statistical analysis was done within groups fed diets without PCB, ascorbic acid deficiency caused significant decreases in body weight gain, hepatic activities of drug-metabolizing enzymes and level of hepatic cytochrome P-450. When OD rats were fed a diet without PCB, the supplementation of about 300 mg ascorbic per kilogram diet was sufficient to maintain normal activities of hepatic aminopyrine N-demethylase, aniline hydroxylase, cytochcrome c reductase and reduction of cytochrome P-450 and a normal level of hepatic cytochrome P-450. However, when OD rats were fed a diet supplemented with 200 mg PCB per kilogram of diet, significantly higher activities of hepatic aminopyrine N-demethylase and aniline hydroxylase and significantly higher level of hepatic cytochrome P-450 were observed in OD rats fed a diet supplemented with 1000 mg or 3000 mg ascorbic acid per kilogram of diet than in rats fed a diet supplemented with 300 mg of ascorbic acid. It is concluded that the dietary requirement of ascorbic acid is increased severalfold by the administration of xenobiotics, such as PCB, for the maximum induction of hepatic drug metabolism.

KEY WORDS: • ascorbic acid • OD rat • xenobiotics • polychlorinated biphenyls (PCB) • drug-metabolism

¹ Supported in part by the grant of Vitamin C Research Committee in Japan.

² To whom reprint requests should be addressed.

Manuscript received 11 February 1986. Revision accepted 16 May 1986.