Inhibitors of human and rat testes microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD) as potential agents for prostatic cancer.
In a screening programme for inhibitors of human testis 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 3), as potential agents for the treatment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17beta-hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profile to recombinant Type 3 17beta-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 microM), phenyl-p-benzoquinone (5.7 microM), 7-hydroxyflavone (9.0 microM), baicalein (9.3 microM) and biochanin A (10.8 microM). Some structure-activity relationships within the flavone/isoflavone series are discussed. Studies with rat testis microsomal 17beta-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.
Le Lain
R
R
Welsh School of Pharmacy, Cardiff University, UK.
Nicholls
P J
PJ
Smith
H J
HJ
Maharlouie
F H
FH
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D044950:Flavanones; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D019833:Genistein / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000201:enzymology*; D013739:Testosterone / Q000378:metabolism
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D004970:Estrone; C029322:phenylbenzoquinone; D013739:Testosterone; D000735:Androstenedione; C006680:baicalein; D004958:Estradiol; C439309:2,5-diphenyl-4-benzoquinone; D019833:Genistein; D015067:17-Hydroxysteroid Dehydrogenases; C004541:biochanin A; C429845:7-hydroxyflavone