Ascorbic acid and hepatic drug metabolism

PH Sato and VG Zannoni

Previous in vivo studies indicate that hepatic microsomal drug metabolism decreases in ascorbic acid deficiency and is augmented when high supplements of the vitamin are given to guinea pigs. Kinetic studies with O-demethylase indicate no significant change in the apparent Km of p-nitroanisole in normal, ascorbic acid-deficient animals, or in animals given high supplements of ascorbic acid. The decrease in drug metabolism activity caused by ascorbic acid deficiency is not due to increased lipid peroxidation, nor was phosphatidyl choline significantly altered quantitatively or qualitatively in microsomes from ascorbic acid-deficient animals. Microsomal cytochrome P-450 prepared from ascorbic acid-deficient livers is less stable to sonication, dialysis and treatment with metal chelators. The decrease in cytochrome P-450 and O-demethylase activity associated with dialysis could be prevented by the addition of ascorbic acid. The molar ratio of microsomal ascorbic acid to cytochrome P-450 (plus P-420) is in the order of 2:1. This ratio is maintained during ascorbic acid deficiency in liver and adrenal tissue, during dialysis, on storage and with a partial purification of the cytochrome, which suggests a close association between ascorbic acid and the cytochrome. In addition, ascorbic acid protects cytochrome P-450 and aniline hydroxy lase activity from inhibition by ferrous iron chelators such as alpha, alpha'-dipyridyl. The chelator binds to cytochrome P-450 and prevents formation of the reduced cytochrome P-450-CO spectrum; it in turn gives a reduced spectrum with the cytochrome at 450 nm. These studies suggest that there is an interaction between ascorbic acid and cytochrome P-450 involving the reduced form of the heme iron.

Volume 198, Issue 2, pp. 295-307, 08/01/1976
Copyright © 1976 by American Society for Pharmacology and Experimental Therapeutics

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