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 3 alpha-hydroxysteroid dehydrogenase (HSD) that can convert 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-adiol) to dih ydrotestosterone (DHT), whose affinity to the androgen receptor is 10(5)-fo ld higher than that of 3 alpha-adiol. The catalytic efficiency of human SCH AD for this oxidative 3 alpha-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 o f 3 alpha-HSD by counteracting all other known 3 alpha-HSDs, which would un idirectionally catalyze the reduction of DHT to the almost inactive 3 alpha -adiol. Human SCHAD is identical to an amyloid-beta binding protein (ERAB) involved in Alzheimer's disease, which was previously reported to be associ ated with the endoplasmic reticulum. This protein is, in fact, localized in mitochondria, not endoplasmic reticulum, as evidenced by immunocytochemica l studies and its noncleavable mitochondrial targeting sequence and lack of endoplasmic reticulum targeting signals or transmembrane segments. These r esults prompt the suggestion that the mitochondrion plays not only an essen tial role in the initial step of steroidogenesis, but also important roles in the intracellular homeostasis of sex steroid hormones. Northern blot ana lysis revealed that the human SCHAD gene is expressed in both gonadal and p eripheral tissues including the prostate whose growth notably requires DHT, the most potent androgen. This study represents the first report of a 3 al pha-HSD that could act to generate DHT from 3 alpha-adiol and thereby maint ain intracellular DHT levels. We propose that inhibitors of the 3 alpha-HSD activity of human brain SCHAD could be useful for the treatment of benign prostatic hyperplasia and other disorders involving DHT metabolism, in comb ination with known inhibitors of steroid 5 alpha-reductases. (C) 2000 Elsev ier Science B.V. All rights reserved.