MOLECULAR ASPECTS OF BRAIN AROMATASE CYTOCHROME-P450

Aromatase cytochrome P450 (P450arom) enzyme activity catalyses the con version of androgens to estrogens in specific brain areas. During cent ral nervous system (CNS) development local estrogen formation influenc es sexual differentiation of neural structures, regulates neuroendocri ne functions and sexual behavior. A proposed mechanism (and re-examina tion) of the sexual differentiation of the rodent brain is presented. The metabolic pathway of androgen metabolism by P450arom was character ized in the medial basal hypothalamic (MBH) tissue from male rats duri ng various prenatal and postnatal developmental intervals. The P450aro m enzyme activity was determined using a saturating concentration of [ H-3]testosterone as the substrate, and the rates were quantified by sc intillation counting. The MBH P450arom activity was highest during pre natal development (i.e. 3-6 pmol/h/mg protein), declined to moderate l evels in newborns and infantile animals (approximately 1 pmol/h/mg pro tein) and then continued to decline to low activity rates in adult ani mals (approximately 80 fmol/h/mg protein). Regulation of the P450arom gene was characterized by a series of molecular biology studies where the controlling mechanism for brain P450arom was determined in MBH and amygdaloid tissue sites. Evidence for brain P450arom-specific mRNA in perinatal rats is presented as well as comparisons with rat ovary, a rat Leydig tumor cell fine (R2C) and human fetal brain P450arom. Speci fically, P450arom gene expression is driven in perinatal rat brain tis sue by a different promoter compared to rat ovarian tissue or a R2C ce ll line, whereas human fetal brain tissue utilizes an almost identical , promoter segment to that observed in the rodent. These findings prov ide an insight into the regulation of brain P450arom gene expression a nd suggest that there is an additional level of control for the expres sion of this gene during perinatal development. However, further study is necessary to understand the molecular basis of this complex develo pmental pattern of brain P450arom expression. (C) 1997 Elsevier Scienc e Ltd.