Regulation of hepatic cytochrome P450 2C11 via cAMP: implications for down-regulation in diabetes, fasting, and inflammation.

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, (S(p))-adenosine 3',5' cyclic monophosphothioate (S(p)-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-beta-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. (R(p))-Adenosine 3',5' cyclic monophosphothioate inhibited the down-regulation of CYP2C11 by S(p)-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.