Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism

Human brain short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) has been demonstrated to be a unique 3alpha-hydroxysteroid dehydrogenase (HSD) that can convert 5alpha-androstane-3alpha, 17beta-diol (3alpha-adiol) to dihydrotestosterone (DHT), whose affinity to the androgen receptor is 10(5)-fold higher than that of 3alpha-adiol. The catalytic efficiency of human SCHAD for this oxidative 3alpha-HSD reaction was estimated to be 164 min(-1) mM(-1), about 10-fold higher than that measured for the backward reaction. Thus, human brain SCHAD may function in androgen metabolism as a new kind of 3alpha-HSD by counteracting all other known 3alpha-HSDs, which would unidirectionally catalyze the reduction of DHT to the almost inactive 3alpha-adiol. Human SCHAD is identical to an amyloid-beta binding protein (ERAB) involved in Alzheimer's disease, which was previously reported to be associated with the endoplasmic reticulum. This protein is, in fact, localized in mitochondria, not endoplasmic reticulum, as evidenced by immunocytochemical studies and its noncleavable mitochondrial targeting sequence and lack of endoplasmic reticulum targeting signals or transmembrane segments. These results prompt the suggestion that the mitochondrion plays not only an essential role in the initial step of steroidogenesis, but also important roles in the intracellular homeostasis of sex steroid hormones. Northern blot analysis revealed that the human SCHAD gene is expressed in both gonadal and peripheral tissues including the prostate whose growth notably requires DHT, the most potent androgen. This study represents the first report of a 3alpha-HSD that could act to generate DHT from 3alpha-adiol and thereby maintain intracellular DHT levels. We propose that inhibitors of the 3alpha-HSD activity of human brain SCHAD could be useful for the treatment of benign prostatic hyperplasia and other disorders involving DHT metabolism, in combination with known inhibitors of steroid 5alpha-reductases.