Antiglucocorticoid activity of 21-OH-6,19-oxidoprogesterone

GRANADO, M; VILLANÚA, M. A.; PECCI, ADALÍ; LANTOS, CARLOS P.; BURTON, GERARDO; TRESGUERRES, JESUS A. F.; LOPEZ-CALDERÓN, A.

Atenas, Grecia

Congreso; 12th International Congress on Hormonal Steroids and Hormones and Cancer; 2006

Mifepristone is an antiglucocorticoid that has a strong antiprogestagenic activity. The aim of this work was to elucidate if 21-hydroxy-6,19-oxidoprogesterone (21OH-6,19-OP) also has antiglucocorticoid activity without the progestagenic effect. To study antiprogestagenic activity, the abortifacient effect of this compound was tested and RU486 was used as positive control. Mice on day 7 of pregnancy were injected once with 0.05 mg RU486, 0,05 or 0.5 mg of 21OH-6,19-OP acetate, control mice received oil sc. On day 11 of pregnancy, the number and condition of foetuses and serum progesterone were analyzed. RU486 cused 100% abortion, whereas 21OH-6,19-OP acetate given at the same dose or 10 times higher had no effect on pregnancy. The number of embryos of the mice injected with 21OH-6,19-OP acetate were identical to those of the control mice. RU486 decreased (p<0.01) serum progesterone, whereas 21OH-6,19-OP acetate did not modify its levels. To evaluate the antiglucocorticoid activity, the effect of 21OH-6,19-OP and RU486 on ACTH release from pituitary cell cultures was examined. Rat pituitary cells were obtained after collagenase digestion, and were incubated in RPMI 1640. After 3 days 21OH-6,19-OP or RU486 at different concentrations were dissolved in medium alone or in medium with dexamethasone (10-7M) during 4 hours. Dexamethasone decreased ACTH release (p<0.05) while 21OH-6,19-OP had no effect on its basal release. In the cells cultured with dexamethasone 10-7M, 21OH-6,19-OP prevented its inhibitory effect at concentrations of 10-8M, 10-7M and 10-6M. However 21OH-6,19-OP was not able to prevent the inhibitory effect of dexamethasone on ACTH at the concentrations of 10-10M or 10-9M. RU486 did not modify basal ACTH release and prevented the inhibitory effect of dexamethasone at all concentrations tested. These data suggest that 21OH-6,19-OP acts as a pure glucocorticoid receptor antagonist without antiprogestagenic or abortifacient activity.