Species Differences in Prostatic Steroid 5α-Reductases of Rat, Dog, and Human

Abstract

The conversion of testosterone to 5.alpha.-dihydrotestosterone by prostate particulates from rats, dogs and humans was investigated, and significant species differences were found with their pH profiles, affinities for 4-azasteroidal inhibitors, and sensitivities to mercuric sulfhydryl reagents. The pH optima for the rat (pH 7), the dog (pH 6) an the human (pH 5) enzyme are significantly different. Mersalyl acid and p-hydroxymercuribenzoate inactivate only the rat 5.alpha.-reductase, but not the human or dog enzyme. The rank orders of potencies of 24 3-oxo-4-azasteroids to inhibit 5.alpha.-reductases of the rat, dog and human prostate are different. The variation of the 17.beta.-functional groups of the inhibitors demonstrates clearly the species differences. Those inhibitors with a 17.beta.-diethylcarbamoyl, 17.beta.-diisopropylcarbamoyl, 17.beta.-butylcarbamoyl or 17.beta.-secbutylcarbonyl functional group are approximately equipotent as inhibitors of the rat and human enzymes; they are only 0.1-15% as potent as inhibitors of the dog enzyme. Those inhibitors with a 17.beta.-spiroether functional group are most potent as inhibitors of the rat enzyme, are 15-50% as potent as inhibitors of the dog enzyme and are 0.2-0.4% as potent as inhibitors of the human enzyme. Those inhibitors with a 17.beta.-n-octylcarbamoyl, 17.beta.-(1-carboxyethyl) or 17.beta.-(1-carboxy-3-butyl) functional group are 2-3 orders of magnitude less potent as inhibitors of the dog and human enzymes than as inhibitors of the rat enzyme. Apparently, prostatic 5.alpha.-reductases of rats, dogs and humans are significantly different. In spite of the significantly species differences in inhibitor affinities, where determined, inhibition of the rat, dog and human enzymes by these compounds is competitive with testosterone. These 3-oxo-4-azasteroids have a similar rank order of potency as inhibitors of 5.alpha.-reductase in human normal, benign hyperplastic, and cancerous prostates, indicating that the inhibitor-binding sites of 5.alpha.-reductase in the prostate in different pathological states are similar. The affinities of the 3-oxo-4-azasteroids for rat prostatic cytosol receptor were determined. Five of these 5.alpha.-reductase inhibitors have no significant affinity for the androgen receptor; others do have an affinity for the receptor.