Different effects of short‐ and long‐term dietary choline‐deficiency on hepatic microsomal phospholipids and drug oxidation

Abstract

Prolonged administration of a choline‐deficient diet to male rats results in the development of hepatic cirrhosis and alterations in oxidative drug metabolism. The present study was designed to assess whether the changes in drug metabolism were related to the development of cirrhosis or merely to the effects of choline‐deficiency on hepatic microsomal lipid composition. Male rats were given a synthetic choline‐deficient diet for either 1 week (short‐term) or 30 weeks (long‐term), and results at each time were compared with age‐matched control rats given the same diet but with supplementary choline.After both 1 week and 30 weeks of the choline‐deficient dietary regimen, the proportion of microsomal phospholipid present as phosphatidylcholine was significantly decreased, and that present as phosphatidylethanolamine was significantly increased, compared with appropriate controls. However, microsomal cholesterol content (per mg of microsomal protein) was not significantly changed at either time. Cytochrome P‐450 levels and the turnover of ethylmorphine N‐demethylase (enzyme activity/nmol cytochrome P‐450) were significantly reduced in the cirrhotic (30 week) model whereas short‐term intake of the diet did not alter the levels of cither enzyme. These findings suggest that the effects of changes in phosphatidylcholine and phosphatidylethanolamine levels in choline‐deficiency cirrhosis have minimal importance with respect to changes in drug oxidation. Instead, altered regulation of specific cytochrome P‐450 isozymes appears to be the principal cause of impaired oxidation.