Glucose consumption by rats decreases cytochrome P450 enzyme activity by altering hepatic lipids

Although glucose is a ubiquitous nutrient, increased consumption of glucose decreases the metabolism of numerous drugs in humans and animals. To understand the mechanisms involved that cause decreased drug metabolism in rats that consume glucose in their water, enzyme activity and expression as well as determining the contribution of the lipids toward decreasing in vitro metabolic activity were investigated. Enzyme assays of hepatic CYP1A2, 2C6, 2C11 and 3A2 showed significant decreases in activity from glucose-treated rats compared to control. While immunodetection of CYP1A1, 2B1/2, 2C11, and 3A1/2 showed no significant difference in protein expression. Hepatic fatty acid synthase activity increased in the glucose-treated rats compared to controls. Studies with glucose-treated microsomal lipids reconstituted with microsomal proteins from control rats caused a significant decrease in benzyloxyresorufin O-dealkylase activity. The results presented here support the hypothesis that the activities of cytochrome P450 proteins are altered by modulating their catalytic activity as a result of the lipid environment rather than changing the level of expression of the individual enzymes.