Abstract
The effect of glucagon and its second messenger cAMP on cytochrome P450 2C11 (CYP2C11) expression was investigated in primary hepatocytes cultured on Matrigel. Glucagon, epinephrine, forskolin, and the cAMP derivatives dibutyryl cAMP, (Sp)-adenosine 3′,5′ cyclic monophosphothioate (Sp-cAMPS), and 8-(4-chlorophenylthio)-cAMP, but not dideoxyforskolin, all down-regulated CYP2C11 mRNA expression to approximately 20% of control levels in a concentration-dependent manner. Using the transcriptional inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole, CYP2C11 mRNA was found to have a half-life of 9.8 h. The kinetics of suppression of CYP2C11 mRNA by glucagon and forskolin was similar to that obtained with the transcriptional inhibitor, suggesting that glucagon and forskolin act at the transcriptional level. CYP2C11 expression was more sensitive to suppression by glucagon at low insulin concentrations than at higher concentrations. (Rp)-Adenosine 3′,5′ cyclic monophosphothioate inhibited the down-regulation of CYP2C11 bySp-cAMPS, consistent with a competitive blockade of protein kinase A activation. These results suggest a role for glucagon in the down-regulation of CYP2C11 in diabetic rats, and provide a possible explanation for the known sensitivity of this cytochrome P450 to suppression in various stress and disease models.
Footnotes
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Send reprint requests to: Edward T. Morgan, Ph.D., Department of Pharmacology, Emory University, Atlanta, GA 30322. E-mail: etmorga{at}bimcore.emory.edu
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This work was supported by Grants GM46897 and T32 DK07298 from the National Institutes of Health.
- Abbreviations:
- P450
- cytochrome P450
- (dB)-cAMP
- dibutyryl cAMP
- CPT-cAMP
- 8-(4-chlorophenylthio)-cAMP
- Sp-cAMPS
- (Sp)-adenosine 3′,5′ cyclic monophosphothioate
- PKA
- cyclic AMP-dependent protein kinase
- Rp-cAMPS
- (Rp)-adenosine 3′,5′ cyclic monophosphothioate
- DRB
- 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole
- SSC
- standard saline citrate
- G/I
- glucagon/insulin
- GH
- growth hormone
- Received November 16, 2000.
- Accepted December 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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