Alterations in drug metabolizing activities in acute hepatosteatosis induced by intake of a high-carbohydrate/fat-free diet after food deprivation

Abstract

Background: Lipid accumulation in hepatocytes constitutes a major component in the pathogenesis of chronic liver injury. However, the impact of lipid deposition in liver on drug metabolizing capacity remains unclear. Purpose of the study: The present study was undertaken to evaluate the changes in hepatic cytochrome P-450 (CYP) enzymes in acute hepatosteatosis. Methods: The rat subjects fasted for 48 h, and then were provided with a high-carbohydrate/fat-free diet (FH) or a normal diet (FN) for 48 h. Results: Hepatic lipid accumulation was significant in the FH group compared to the FN group. In the FN group, there was a small increase in microsomal p-nitrophenol hydroxylase, pnitroanisole O-demethylase, and erythromycin N-demethylase activities. In contrast, aminopyrine N-demethylase activity significantly decreased. However, the microsomal enzyme activities were all inhibited by FH intake. Immunoblotting analysis revealed that CYP2E1, CYP1A, CYP3A, and CYP2B1/2 proteins decreased in the FH group. Expression of corresponding CYP mRNAs was also down-regulated. A dose of CCl4, a CYP2E1 substrate, was administered to rats fed with different diets. The liver injury was significantly lower in the FH group compared to the FN group, as determined by the elevation of serum enzyme activities and histopathological examination. Conclusions: The results revealed that acute hepatosteatosis may result in a significant alteration in hepatic CYP-mediated metabolizing capacity, which can precipitate erratic responses of liver to various endogenous and exogenous substances.