Metabolic Fate of Androgens in the Pineal Organ: Uptake, Binding to Cytoplasmic Proteins and Conversion of Testosterone into 5α-Reduced Metabolites

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Abstract
The pinneal organs of orchiectomized rats incubated in vitro with 3H-testosterone took up and retained 3H-radioactivity up to a tissue concentration 18-fold that of the incubation media. Maxima in tissue/medium ratios (T/M) were observed after 2-hr incubations at 37 C. Pineal organs of castrated rats exhibited higher T/M ratios than sham-operated controls. Pineal T/M ratio was 8- and 6-fold that of the cerebral cortex and tibial muscle, respectively, and about half that of the prostate. Testosterone, β-hydroxy-5α-androstan-3-one, 5α-androstane-3α, 17β-diol, androstenedione, and 5α-androstane-3, 17-dione were identified in the incubated rat pineals by thin-layer chromatography and recrystallization to constant specific activity. At low concentrations of testosterone (up to 2 × 10−11 M), T/M ratios for 3H-radioactivity depended upon the concentration of the hormone in the incubation medium. At higher concentrations pineal T/M ratio remained constant regardless of the concentration of testosterone in the medium. Treatment with dextran-coated charcoal of cytosol fractions of rat pineal homogenates incubated with 3H-testosterone of different SA uncovered a high affinity, low capacity binding of the hormone to cytosol components. Saturation kinetics analysis of the 105,000 × g supernatant of bovine pineal organs indicated a dissociation constant for high affinity binding sites of (1.57 ± 0.40) × 10−9 M for testosterone and (0.36 ± 0.09) × 10-9 M for β/3-hydroxy- 5α-androstan-3-one; the concentration of binding sites was 9 ± 3 and 43 ± 5 femtomoles/mg of cytosol protein, respectively. Trypsin, but not ribonuclease, abolished androgen binding; iodacetamide decreased binding activity significantly. By charcoal assay the following order of affinity was found: 17β-hydroxy- 5α-androstan-3-one > testosterone > androstenedione > estradiol > 5α-androstane-3,β-dione > 5α-androstane-3,17-diol. Progesterone, cortisol and corticosterone did not affect androgen binding significantly. Nuclear uptake of 3H-radioactivity in rat pineal cells also depended upon testosterone concentration in medium; 17β-hydroxy-5α-androstan-3-one was the major metabolite present in nuclear extracts of incubated rat pineals. These results, together with our previous observations in vivo, suggest that the pineal gland is a target organ for androgens. (Endocrinology95: 179, 1974)

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