Cyclosporine and bromocriptine-induced suppressions of CYP3A1/2 and CYP2C11 are not mediated by prolactin.
The purpose of this study was to determine if the suppression of hepatic CYP3A1/2 (cytochrome P450 3A1/2) and CYP2C11 (cytochrome P450 2C11) by cyclosporine is mediated by prolactin. Male intact rats were given subcutaneous doses of either 15 mg/kg/day of cyclosporine or 1 ml/kg/day of cyclosporine vehicle concomitantly with one of the following: 500 mg/kg prolactin, 1 ml/kg prolactin vehicle, 4 mg/kg bromocriptine, or 1 ml/kg bromocriptine vehicle for 14 days. Protein expressions were measured using Western blot analysis and activities were measured using an in vitro testosterone hydroxylation assay. The administration of prolactin did not significantly alter CYP3A1/2 protein expression. Hypoprolactinemia, produced by bromocriptine, caused a significant suppression of CYP3A1/2 activity levels when bromocriptine was administered alone and in combination with cyclosporine (P<0.001, P<0.05; respectively). However, the cause of the suppression by bromocriptine was likely not the result of lowering prolactin levels. Bromocriptine administration also lowered CYP2C11 protein expression and activity, while prolactin administration had virtually no effect on CYP2C11. Chronic cyclosporine administration caused a 140% increase in prolactin area under the curve (AUC) (P<0.001). Bromocriptine caused a significant decline in endogenous prolactin secretion, however, concurrent cyclosporine administration did not recover these levels. Overall, while both cyclosporine and bromocriptine, separately, can significantly alter the fate of hepatic P450 enzymes, the suppression is likely not due to an alteration in prolactin levels.
Lu
Shirley K
SK
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, PHR 4.214E 1 University Station A1920, Austin, TX 78712-1074, USA.
Callahan
Shellie M
SM
Jin
Runyan
R
Brunner
Lane J
LJ
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001971:Bromocriptine / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D001971:Bromocriptine; D016572:Cyclosporine; D011388:Prolactin; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase