Inhibitors of human and rat testes microsomal 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) as potential agents for prostatic cancer

In a screening programme for inhibitors of human testis 17 beta -hydroxyste roid dehydrogenase (17 beta -HSD type 3), as potential agents for the treat ment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17 beta -hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profi le to recombinant Type 3 17 beta -HSD from the same source as determined by the low K-m/V-max ratio for the reduction of androstenedione compared to t he oxidation of testosterone, and a low level of activity in reduction of o estrone. Screening of a wide range of compounds of different structural typ es as potential inhibitors of the microsomal enzyme in the reduction step r evealed that certain p-benzoquinones and flavones/isoflavones were potent i nhibitors of the enzyme, diphenyl-p-benzoquinone (2.7 muM), phenyl-p-benzoq uinone (5.7 muM), 7-hydroxyflavone (9.0 muM), baicalein (9.3 muM) and bioch anin A (10.8 muM). Some structure-activity relationships within the flavone /isoflavone series are discussed. Studies with rat testis microsomal 17 bet a -HSD showed that it differed from the human enzyme mainly in its greater ability to accept oestrone as substrate and the pH-optimum for oxidation of testosterone. It was found to be much less sensitive to inhibition by the compounds studied so negating it use as a more readily available tissue for the screening of potential inhibitors.