Poletti A, Negri-Cesi P, Rabuffetti M, Colciago A, Celotti F, Martini L
Istituto di Endocrinologia, Università di Milano, Milan, Italy.
Endocrinology. 1998 Apr;139(4):2171-8. doi: 10.1210/endo.139.4.5866.
The enzyme 5alpha-reductase plays a key role on several brain functions controlling the formation of anxiolytic/anesthetic steroids derived from progesterone and deoxycorticosterone, the conversion of testosterone to dihydrotestosterone, and the removal of excess of potentially neurotoxic steroids. Two 5alpha-reductase isoforms have been cloned: 5alpha-reductase type 1 is widely distributed in the body, and 5alpha-reductase type 2 is confined to androgen-dependent structures. In this study, the gene expression of the two 5alpha-reductase isozymes has been analyzed in fetal, postnatal, and adult rat brains by RT-PCR followed by Southern analysis. 5Alpha-reductase type 1 messenger RNA is always detectable in the rat brain [from gestational day 14 (GD14) to adulthood]. 5Alpha-reductase type 2 messenger RNA expression is undetectable on GD14, increases after GD18, peaks on postnatal day 2, then decreases gradually, becoming low in adulthood. This pattern of expression appears to be correlated with the rate of production of testosterone by the testis. The possible control by androgens of gene expression of the two isozymes has been studied in brain tissues of animals exposed in utero to the androgen antagonist flutamide; the sex of the animals was determined by genetic sex screening of the SRY gene located on the Y-chromosome. In the brain of male embryos, flutamide treatment inhibited the expression of 5alpha-reductase type 2; this effect was much less pronounced in females. Moreover, 5alpha-reductase type 2 gene expression in cultured hypothalamic neurons is highly induced by testosterone and by the phorbol ester 12-O-tetradecanoyl-phorbol-13 acetate. The transient, androgen-regulated, expression of 5alpha-reductase type 2 overlaps the critical period of development, which may be important for sexual differentiation of the brain and for the formation of anxiolytic/anesthetic steroids involved in the stress responses associated with parturition.
5α-还原酶在多种脑功能中发挥关键作用，它控制着源自孕酮和脱氧皮质酮的抗焦虑/麻醉性甾体的形成、睾酮向二氢睾酮的转化以及清除过量潜在神经毒性甾体。已克隆出两种5α-还原酶同工型：1型5α-还原酶广泛分布于体内，2型5α-还原酶局限于雄激素依赖结构。在本研究中，通过逆转录聚合酶链反应（RT-PCR）及随后的Southern分析，对胎鼠、新生鼠和成年大鼠脑内两种5α-还原酶同工酶的基因表达进行了分析。1型5α-还原酶信使核糖核酸在大鼠脑内始终可检测到（从妊娠第14天到成年）。2型5α-还原酶信使核糖核酸在妊娠第14天不可检测，在妊娠第18天后增加，在出生后第2天达到峰值，然后逐渐下降，成年后变得很低。这种表达模式似乎与睾丸产生睾酮的速率相关。在子宫内暴露于雄激素拮抗剂氟他胺的动物脑组织中，研究了雄激素对两种同工酶基因表达的可能调控；通过对位于Y染色体上的SRY基因进行遗传性别筛查来确定动物的性别。在雄性胚胎脑中，氟他胺处理抑制了2型5α-还原酶的表达；这种作用在雌性中不太明显。此外，培养的下丘脑神经元中2型5α-还原酶基因表达受到睾酮和佛波酯12-O-十四烷酰佛波醇-13-乙酸酯的高度诱导。2型5α-还原酶短暂的、受雄激素调节的表达与发育关键期重叠，这可能对脑的性分化以及参与分娩相关应激反应的抗焦虑/麻醉性甾体的形成很重要。
