Poletti A, Martini L
Istituto di Endocrinologia, Università di Milano, Milan, Italy.
J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):117-22. doi: 10.1016/s0960-0760(98)00150-2.
In the rat brain, several steroids can be converted by specific enzymes to either more potent compounds or to derivatives showing new biological effects. One of the most studied enzyme is the 5alpha-reductase (5alpha-R), which acts on 3keto-delta4 steroids. In males, testosterone is the main substrate and gives rise to the most potent natural androgen dihydrotestosterone. In females, progesterone is reduced to dihydroprogesterone, a precursor of allopregnanolone, a natural anxiolytic/anesthetic steroid. Other substrates are some gluco- and minero-corticoids. Two isoforms of the 5alpha-R, with limited degree of homology, have been cloned: 5alpha-R type 1 and type 2. The 5alpha-R type 1 possesses low affinity for the various substrates and is widely distributed in the body, with the highest levels in the liver; in the brain, this isoform is expressed throughout life and does not appear to be controlled by androgens. 5Alpha-R type 1 in the rat brain is mainly concentrated in myelin membranes, where it might be involved in the catabolism of potentially neurotoxic steroids. The 5alpha-R type 2 shows high affinity for the various substrates, a peculiar pH optimum at acidic values and is localized in androgen-dependent structures. In the rat brain, the type 2 isoform is expressed at high levels only in the perinatal period and is controlled by androgens, at least in males. In adulthood, the type 2 gene appears to be specifically expressed in localised brain regions, like the hypothalamus and the hippocampus. The 5alpha-R type 2 is present in the GT1 cells, a model of LHRH-secreting neurons. These cells also contain the androgen receptor, which is probably involved in the central negative feedback effect exerted by androgens on the hypothalamic-pituitary-gonadal axis. The physiological significance of these and additional data will be discussed.
在大鼠脑中，几种甾体可被特定酶转化为更强效的化合物或具有新生物学效应的衍生物。研究最多的一种酶是5α-还原酶（5α-R），它作用于3-酮-δ4甾体。在雄性中，睾酮是主要底物，可生成最强效的天然雄激素双氢睾酮。在雌性中，孕酮被还原为双氢孕酮，它是别孕烯醇酮的前体，别孕烯醇酮是一种天然的抗焦虑/麻醉甾体。其他底物是一些糖皮质激素和盐皮质激素。已克隆出5α-R的两种同源性有限的同工型：5α-R 1型和2型。5α-R 1型对各种底物的亲和力较低，在体内广泛分布，肝脏中含量最高；在脑中，这种同工型终生表达，似乎不受雄激素调控。大鼠脑中的5α-R 1型主要集中在髓鞘膜中，可能参与潜在神经毒性甾体的分解代谢。5α-R 2型对各种底物具有高亲和力，在酸性值时有独特的最适pH，且定位于雄激素依赖结构中。在大鼠脑中，2型同工型仅在围产期高水平表达，且至少在雄性中受雄激素调控。在成年期，2型基因似乎在特定脑区如下丘脑和海马体中特异性表达。5α-R 2型存在于GT1细胞中，GT1细胞是促性腺激素释放激素分泌神经元的模型。这些细胞还含有雄激素受体，雄激素受体可能参与雄激素对下丘脑-垂体-性腺轴的中枢负反馈作用。将讨论这些及其他数据的生理学意义。
