Androgens control the development, growth and function of target tissues, such as the prostate, a major site of both benign and malignant growth in men. 5a-Reductase converts testosterone, the major circulating androgen in men, to dihydrotestosterone, a process believed to amplify the androgenic signal. Two different isozymes of 5a-reductase are present in rats, humans and other animals. The type 2 isozyme is critical for normal male development. Androgenic responses may depend on which isozyme is in a cell and this will be tested with an androgen-responsive reporter gene in cells designed to express components of this system. Testosterone and dihydrotestosterone may also control the expression of separate genes and this possibility will be investigated. Excessive dihydrotestosterone or 5a-reductase activity has been implicated in a variety of androgen-dependent pathological conditions including benign prostatic hyperplasia, acne, alopecia, and female idiopathic hirsutism. Inhibition of 5a-reductase has been proposed as a method to treat these conditions as well as a chemopreventative for prostate cancer, since the growth and function of this gland is dependent on dihydrotestosterone and most prostate cancers are initially androgen-dependent. Although a variety of synthetic 5a-reductase inhibitor have been developed, the first of these to be tested clinically (finasteride) has had limited efficacy. A variety of natural compounds that inhibit 5a-reductase in vitro have been identified. Some of these compounds are pytochemicals that are part of our diet. These compounds may modulate 5a-reductase activity in vivo and in so doing alter normal and malignant cellular growth and function. Naturally occurring 5a-reductase inhibitors and synthetic analogs will be tested in bioassays including growth and function of normal and malignant cells in culture, testosterone-induced accessory sex gland growth in rats and androgen-dependent growth of hamster sebaceous glands. The effect of these 5a-reductase inhibitors on the growth of androgen-dependent human prostate tumors xenografts in nude mice will be examined. Very little is known about the functional domains of 5a-reductase or the mechanism by which this enzyme reduces its various substrates. Development of new inhibitors of this enzyme as well as understanding the mechanism of inhibition of those inhibitors presently in hand would benefit from a more detailed picture of the steroid-binding domain of this protein. A recently developed photoaffinity-label will be used to identify amino acid residues in the steroid-binding domain of the isozymes.
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