Experimental Studies of the Effects of Progesterone on the Functional Activity of P-Glycoprotein

Abstract

Experiments on female Chinchilla rabbits addressed the effects of progesterone on the functional activity of P-glycoprotein (Pgp). Animals were divided into four groups: animals of group 1 underwent sham operations; group 2 underwent ovariectomy; groups 3 and 4 underwent ovariectomy followed 15 days later by p.o. treatment with progesterone (2 and 15 mg/rabbit respectively). The functional activity of Pgp was determined seven days before the experiment started and on post-operative days 14, 28, and 42 by analysis of the pharmacokinetics of its marker substrate fexofenadine and serum sex hormone concentrations. At the end of the study, animals of each group were harvested by air embolism and specimens of large intestine were collected for immunohistochemical analysis. Ovariectomy led to a decrease in the functional activity of Pgp and a decrease in the staining intensity of the apical and lateral membranes of enterocytes, providing indirect evidence of a decrease in the expression of the transporter protein. Administration of progesterone at a dose of 2 mg/rabbit on the background of ovariectomy increased the functional activity of Pgp from the level seen in the ovariectomy group, though its activity remained decreased compared with the baseline level. This group showed no changes in the staining intensity of enterocyte membranes as compared with the ovariectomy group. Use of progesterone at a dose of 15 mg/rabbit after ovariectomy increased the functional activity of Pgp and the staining intensity of enterocyte apical and lateral membranes from the level seen in the ovariectomy group, restoring the level of transporter protein activity to that of intact animals, probably because of increased expression.