Pronounced effects of cyclosporin A and NVA2-cyclosporin on hepatic steroid metabolism and endocrine parameters in male Sprague-Dawley rats.

Cyclosporin A (CsA) and the analogue NVA2-cyclosporin (NVA2-Cs) were administered by daily injections (i.p.) to male Sprague-Dawley rats for 7 days. At the 5 mg/kg dose level a significant increase in the ratio between 5 alpha-reduction and 16 alpha-hydroxylation of 4-androstene-3,17-dione was observed with both compounds. Serum levels of corticosterone were significantly increased in these rats. A daily dose of 50 mg/kg gave rise to more pronounced changes in the metabolism of 4-androstene-3,17-dione, with an almost 10-fold increase in the 5 alpha/16 alpha-ratio and a decrease in 6 beta-hydroxylation. At the high dose level serum levels of corticosterone increased greater than 2-fold, whereas testosterone decreased. This decrease was more pronounced with CsA treatment (greater than 40-fold) than with NVA2-Cs (greater than 3-fold). A significant decrease in the serum levels of luteinizing hormone (LH) was observed with high dose CsA treatment. High dose CsA and NVA2-Cs reduced serum prolactin levels, 6- and 3.6-fold, respectively. A small but significant increase in the serum level of creatinine was observed only in rats receiving NVA2-Cs, 50 mg/kg. The changes in hepatic steroid-metabolizing enzymes following CsA and NVA2-Cs treatment indicate that both compounds influence male rat liver via neuroendocrine mechanisms previously shown to regulate a number of hepatic functions, including several steroid-metabolizing enzymes. These functions are regulated from the hypothalamus, through the secretory pattern of growth hormone. The observed effects of CsA and NVA2-Cs might be due to an indirect action on growth hormone secretion, where an altered testosterone production exerts an influence at the hypothalamic level, and/or the result of a direct effect on the hypothalamus.