Stimulation of Ribonucleic Acid Polymerase Activity in Mouse Kidney*

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Abstract
As part of an ongoing study to determine the mechanisms that differentiate between the agonistic and antagonistic effects of steroids, several natural and synthetic compounds that bind to the androgen receptor were evaluated for their effects on renal nuclear RNA polymerase I and II activities. The androgenic progestin 6α-methyl-progesterone (6MP) as well as the antiandrogens cyproterone acetate (6-chloro-17α-acetoxyl-l,2α-methylene-4,6-pregnadiene-3,20-dione) and flutamide (4′-nitro-3′-trifluoromethylisobutyrylanilide) and ineffective steroids 17α-hydroxy-6MP and progesterone were studied using normal and Tfm/Y mice, which lack effective androgen receptors. In normal mice, a single dose of 6MP stimulated a biphasic pattern of early (30 min) and late (16–24 h) increases in the activities of RNA polymerase I and II, which was similar to the responses induced by testosterone and medroxyprogesterone acetate (6α-methyl-17α-acetoxy-4-pregnene-3,20-dione). Cyproterone acetate stimulated an early increase in polymerase I activity, which remained elevated during the 24 h of study. Polymerase II responded in a biphasic manner. Flutamide stimulated only late changes in polymerase activities. The response of 17α-hydroxy-6MP was more pronounced during the initial hours of stimulation, whereas progesterone was more effective later on. When the compounds were administered daily for 4 days, all compounds, with the exception of 17α-hydroxy-6MP, maintained increased levels of polymerase activities regardless of their effects on androgen responses. In Tfm/Y mice, 6MP, but not testosterone or flutamide, stimulated early and late increases in polymerase I and II activities. This correlates with a previous finding of renal nuclear retention of 6MP in these mice. Thus, there was, no close correlation between a compound's biological effect (androgenic, antiandrogenic, or ineffective) and its ability to at least initiate a nuclear response. Subtle differences may be important, however, as the biphasic response induced by androgenic steroids was not mimicked by antiandrogens or ineffective compounds.