Heme oxygenase activity, drug metabolism, and ascorbic acid distribution in the livers of ascorbic acid-deficient guinea pigs

Abstract

The influence of ascorbic acid (AA) on microsomal heme oxygenase (MHO) (EC 1.14.99.3). drug metabolism and AA distribution was studied in livers and liver cytosols isolated from guinea pigs. Aminopyrine N-demethylase and cytochrome P-450 content were examined in guinea pigs on days 0,6,12 and 19 after being placed on a basal diet deficient in AA. Plasma AA seems to reflect total liver AA; however, AA from the liver cytosol (100,000 g soluble fraction) component decreased at a slower rate than total liver AA as deficiency progressed. The decrease in hepatic aminopyrine N-demethylase and in cytochrome P-450 content was related to the decrease in cytosolic AA. Perfusion of livers from guinea pigs not depleted of AA resulted in a 71 per cent loss of extracellular AA. Liver perfusions also resulted in 26.2 and 16.0 per cent decreases in cytochrome P-450 content from AA-deficient and AA-supplemented guinea-pigs (25 mg/100g) respectively. These data suggest that a labile soluble pool of AA may have some influence on cytochrome P-450 content and drug metabolism. MHO activity was decreased significantly (P < 0.05) in the livers from AA-deficient guinea pigs compared to AA-supplemented guinea pigs. In a separate experiment, guinea pigs were given either the basal diet alone or the basal diet and either 1 or 50 mg AA/100 g for 28 days. MHO activity was found to increase significantly with increasing doses of AA (P < 0.005). These results suggest a dose-related dependence of MHO on AA and that AA deficiency does not produce an increase in hepatic heme catabolism via increased MHO activity.