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Posttranscriptional elevation of cytochrome P450 3A expression
R C Zangar1, M Hernandez, R F Novak
1Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Biochemical and Biophysical Research Communications
|February 3, 1997
Summary
Dimethyl sulfoxide (DMSO) selectively increases the protein levels of hepatic CYP3A and CYP2E1 enzymes in rats. This occurs through posttranscriptional mechanisms, without affecting mRNA, indicating a specific regulatory pathway.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Cytochrome P450 enzymes, particularly CYP3A, are crucial for metabolizing xenobiotics.
- Dimethyl sulfoxide (DMSO) is a widely used solvent with therapeutic applications.
- Understanding DMSO's impact on drug-metabolizing enzymes is vital for safety and efficacy.
Purpose of the Study:
- To investigate the effects of dimethyl sulfoxide (DMSO) on the expression of key cytochrome P450 enzymes (CYP3A, CYP2E1, CYP2B) and NADPH cytochrome P450 reductase.
- To determine if these effects occur at the protein or mRNA level and if they are selective.
Main Methods:
- Treatment of rats and primary cultured rat hepatocytes with dimethyl sulfoxide.
- Quantification of CYP3A, CYP2E1, CYP2B, and NADPH cytochrome P450 reductase protein levels using immunodetection.
- Analysis of corresponding mRNA levels.
Main Results:
- Dimethyl sulfoxide significantly increased hepatic CYP3A and CYP2E1 protein levels (2.5-3 fold) without altering their mRNA levels.
- No changes were observed in CYP2B or NADPH cytochrome P450 reductase expression, indicating selective effects.
- DMSO also enhanced CYP3A protein in dexamethasone-pretreated rats and in cultured hepatocytes, independent of mRNA changes.
Conclusions:
- Dimethyl sulfoxide enhances CYP3A and CYP2E1 expression via posttranscriptional mechanisms.
- These findings are relevant to human exposure levels and highlight DMSO's selective impact on specific P450 enzymes.