Abstract: Several authors have suggested that low progesterone concentrations contribute to pregnancy loss, an affect that may result from abnormally high progesterone catabolism. Recently, we demonstrated, in vitro, that increasing insulin concentrations caused a dose-dependent decrease in progesterone catabolism by hepatocytes. The objectives of this study were to determine if CYP2C, CYP3A or both enzymes were responsible for the insulin mediated alteration in progesterone catabolism. A dose-dependent decrease in CYP2C and CYP3A activity was observed in hepatocytes challenged with increasing concentrations of insulin, while a challenge with glucagon did not affect cytochrome P450 2C or 3A activity. As expected, due to the progesterone catabolizing properties of CYP2C and CYP3A, we found elevated concentrations of progesterone in the media of hepatocyte cell cultures that contained insulin, while a challenge with glucagon had no affect on progesterone concentrations. Cytochrome P450 2C activity was decreased during exposure of cells to 1.0 nM insulin and 0.1 nM glucagon as well as to 0.1 nM insulin and 1.0 nM glucagon. Cells cultured with 1.0 nM insulin and 0.1 nM glucagon showed a trend for a decrease in CYP3A activity. Cells that had a decrease in the activity of both CYP2C and CYP3A after a challenge with both insulin and glucagon had elevated progesterone concentrations. These data support a model in which the insulin-induced decrease in progesterone catabolism is a result of reductions in both CYP2C and CYP3A activity.
Caleb O. Lemley , Jill M. Koch , Kenneth P. Blemings and Matthew E. Wilson , 2009. Alterations in Progesterone Catabolic Enzymes, CYP2C and CYP3A, in Hepatocytes Challenged with Insulin and Glucagon. Journal of Animal and Veterinary Advances, 8: 39-46.