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

Abstract

In a screening programme for inhibitors of human testis 17β-hydroxysteroid dehydrogenase (17β-HSD type 3), as potential agents for the treatment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17β-hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profile to recombinant Type 3 17β-HSD from the same source as determined by the low Km/Vmax ratio for the reduction of androstenedione compared to the oxidation of testosterone, and a low level of activity in reduction of oestrone. Screening of a wide range of compounds of different structural types as potential inhibitors of the microsomal enzyme in the reduction step revealed that certain p-benzoquinones and flavones/isoflavones were potent inhibitors of the enzyme, diphenyl-p-benzoquinone (2.7 μM), phenyl-p-benzoquinone (5.7 μM), 7-hydroxyflavone (9.0 μM), baicalein (9.3 μM) and biochanin A (10.8 μM). Some structure-activity relationships within the flavone/isoflavone series are discussed. Studies with rat testis microsomal 17β-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.