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.
Blanck
A
A
Department of Medical Nutrition, Huddinge University Hospital, Sweden.
Assefaw-Redda
Y
Y
Eneroth
P
P
Bäckman
L
L
D000735:Androstenedione / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003345:Corticosterone / Q000097:blood; D016572:Cyclosporine; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005260:Female; D006728:Hormones / Q000097:blood / Q000378:metabolism*; D006900:Hydroxylation; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D039181:Steroid 16-alpha-Hydroxylase; D013739:Testosterone / Q000097:blood
D003524:Cyclosporins; D006728:Hormones; D013739:Testosterone; D000735:Androstenedione; C045571:cyclosporin G; D016572:Cyclosporine; D011388:Prolactin; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D003345:Corticosterone