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Induction of hepatic microsomal cytochrome P450 by dexamethasone in rhesus monkey (Macaca mulatta)
1Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Abstract:
Intraperitoneal administration of 150 mg dexamethasone (DEX) Kg-1 body wt for four days to rhesus monkeys resulted in statistically significant increases in the activities of hepatic tyrosine aminotransferase (3 fold), microsomal cytochrome P450 (2 fold) and erythromycin N-demethylase (4 fold), but no change in the activities of aminopyrine N-demethylase and NADPH cytochrome c reductase. Three peaks were obtained from control or DEX-treated monkey livers on fractionation of detergent solubilized microsomes by anion exchange chromatography on DE-52. Peak II obtained from DEX-treated monkey microsomes on DE-52 demonstrated the highest specific activity of cytochrome P450 (5.84 nmol mg-1 protein) as compared to other peaks from the same microsomes or any of the peaks obtained from the control microsomes. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the microsomes from control and experimental animals and peak II obtained after anion exchange chromatography of DEX-treated microsomes demonstrated the intensification of two polypeptides of 52.5 and 50 kDa. The results indicate that DEX is an inducer of cytochrome P450 and dependent erythromycin N-demethylase in non-human primate, Macaca mulatta.
Insights
Dexamethasone (DEX) significantly increased hepatic cytochrome P450 and erythromycin N-demethylase activity in rhesus monkeys. DEX acts as an inducer of these key drug-metabolizing enzymes in non-human primates.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Dexamethasone (DEX) is a synthetic glucocorticoid with known effects on drug metabolism.
- Understanding the impact of DEX on hepatic enzyme activity is crucial for predicting drug interactions and toxicity.
Purpose of the Study:
- To investigate the effect of dexamethasone administration on specific hepatic enzyme activities in rhesus monkeys (Macaca mulatta).
- To characterize the changes in cytochrome P450 and related enzyme activities following DEX treatment.
Main Methods:
- Rhesus monkeys received intraperitoneal injections of dexamethasone (150 mg/Kg body weight) for four days.
- Hepatic microsomes were isolated and fractionated using anion exchange chromatography (DE-52).
- Enzyme activities (tyrosine aminotransferase, cytochrome P450, erythromycin N-demethylase, aminopyrine N-demethylase, NADPH cytochrome c reductase) were measured.
- Protein analysis was performed using SDS-PAGE.
Main Results:
- DEX administration led to significant increases in hepatic tyrosine aminotransferase (3-fold), cytochrome P450 (2-fold), and erythromycin N-demethylase (4-fold) activities.
- No significant changes were observed in aminopyrine N-demethylase or NADPH cytochrome c reductase activities.
- Anion exchange chromatography revealed a specific peak (Peak II) from DEX-treated microsomes with the highest cytochrome P450 specific activity.
- SDS-PAGE indicated the intensification of two polypeptides (52.5 and 50 kDa) in DEX-treated microsomes and Peak II.
Conclusions:
- Dexamethasone acts as an inducer of cytochrome P450 and erythromycin N-demethylase in the non-human primate Macaca mulatta.
- These findings highlight DEX's role in modulating drug-metabolizing enzymes, with implications for pharmacokinetic studies in primates.