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Hepatic drug metabolism during development in food-restricted female Sprague-Dawley rats
1Department of Pharmacology, University of Montreal, Quebec, Canada.
Insights
Caloric restriction in female rats significantly altered drug metabolism enzymes, particularly increasing NADPH cytochrome c reductase activity. These dietary effects on hepatic drug metabolism were observed consistently across short and long-term interventions.
Area of Science:
- Pharmacology
- Toxicology
- Nutritional Science
Background:
- Hepatic drug metabolism is crucial for xenobiotic detoxification.
- Caloric restriction is known to influence aging and metabolic processes.
- Understanding the impact of diet on drug metabolism is vital for predicting drug efficacy and toxicity.
Purpose of the Study:
- To investigate the short- and long-term effects of caloric restriction on hepatic drug metabolism in female Sprague-Dawley rats.
- To determine how age and dietary intervention influence key drug-metabolizing enzymes and microsomal components.
Main Methods:
- Female Sprague-Dawley rats were fed ad libitum or a restricted diet from one month of age.
- Hepatic drug metabolism was assessed at 1.5, 4.5, and 12 months of age.
- Measurements included cytochrome P-450 content, NADPH cytochrome c reductase activity, aniline hydroxylase, aminopyrine N-demethylase, and glutathione S-transferase activity.
Main Results:
- Caloric restriction significantly increased NADPH cytochrome c reductase activity at all time points.
- Aniline hydroxylase activity was significantly reduced in restricted diet groups compared to controls.
- Aminopyrine N-demethylase showed age-dependent changes, decreasing in restricted rats but increasing at 1.5 months.
- Microsomal cholesterol, phospholipid content, and their ratio were not affected by diet.
Conclusions:
- Hepatic drug metabolism in female Sprague-Dawley rats shows minimal age-related changes between 1.5 and 12 months.
- Caloric restriction significantly alters specific drug-metabolizing enzymes, with effects varying by enzyme.
- The observed changes in drug metabolism due to dietary restriction were consistent across short- and long-term interventions.
Abstract:
Hepatic drug metabolism was investigated in female Sprague-Dawley rats fed ad libitum (A) or a restricted diet (R) (implemented from age 1 month), at 1.5, 4.5 and 12 months to determine the short- and long-term effects of caloric restriction. Microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were not modified by age. While dietary restriction did not affect cytochrome P-450, it significantly increased NADPH cytochrome c reductase activity at all time periods when compared to corresponding A-fed groups. Aniline hydroxylase and aminopyrine N-demethylase activity tended to decrease with age in the A-fed groups but the differences did not prove to be statistically significant. A significant decrease of aminopyrine N-demethylase was observed with age in R rats. A significant reduction of aniline hydroxylase activity was noted in the R groups compared to age-matched A-fed controls. In contrast, aminopyrine N-demethylase activity increased significantly, but only at 1.5 months of age. Glutathione S-transferase activity was augmented between 1.5 and 4.5 months of age, and this was followed by a significant decrease at age 12 months in both A and R groups. Dietary restriction had no effect on this enzymatic activity. The microsomal cholesterol and phospholipid content as well as the cholesterol/phospholipid molar ratio changed significantly between 1.5 and 4.5 months of age but not between 4.5 and 12 months of age. These parameters were unaltered by dietary restriction. In conclusion, in the female Sprague-Dawley rat there are no statistically significant changes in hepatic microsomal components and drug metabolizing capacity between 1.5 and 12 months of age. Dietary restriction resulted in significant changes in enzymes related to drug metabolism which varied with the enzyme examined. In general, these changes were similar after short- or long-term dietary intervention.