The effects of xanthines on mouse liver cell

Abstract

Pretreatment of mice with caffeine or theophylline for 3 days (100 mg/kg, intraperitoneally, twice daily) resulted in an increase in microsomal protein, RNA content, and cytochrome P-450 content. Caffeine but not theophylline also shortened the duration of action of pentobarbital in mice. Both xanthines, however, had no effect on the onset and duration of action of hexobarbital in these animals. Chemical measurements revealed that the activities of two drug-metabolizing enzymes, aminopyrine N-demethylase and p-nitroanisole O-demethylase, were markedly increased by this schedule of pretreatment with caffeine but slightly increased by theophylline. Further, it was found that the inductive effect of caffeine, but not of theophylline, was accompanied by complete depletion of glycogen granules in the liver and a high degree of proliferation of the smooth endoplasmic reticulum. This effect on glycogen depletion, which was followed by an elevation of blood glucose, may be the result of caffeine inhibition on hepatic phosphodiesterase, because the cyclic AMP content was more than doubled in caffeine-treated hepatocytes. It was concluded that the stronger stimulatory effect of caffeine on drug metabolism than theophylline might be attributed to a much more pronounced proliferation of hepatic endoplasmic reticulum caused by caffeine. © 1974.