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S. C. Stillman, B. A. J. Evans and I. A. Hughes

ABSTRACT

Human genital skin fibroblasts were used to study aromatase activity by analysing the [3H]H2O released as [1β-3H]androstenedione is converted to oestrone. 4-Hydroxyandrostenedione was shown to be a competitive inhibitor of this aromatase activity, the concentration of inhibitor producing 50% inhibition being 1·29 nmol/l. Dexamethasone stimulated the enzyme complex in a dose-dependent manner with half-maximal stimulation at 11·5 nmol/l. A peak of induction occurred after 16 h of preincubation. Measurement of aromatase activity in normal cell strains provided a normal range for the Michaelis–Menten constant (K m) and the maximum velocity (V max) of 6·72±0·54 nmol/l and 215·3±33·9 fmol/mg protein per h (means ± s.e.m., n = 20) respectively. K m values obtained for partial and complete androgen insensitivity syndrome (PAIS and CAIS) patient cell strains were all within the normal range. The mean Vmax±s.e.m. in cell strains from patients with PAIS (n = 13) and CAIS (n = 11) were 127·4±19·2 and 54·8±19·3 fmol/mg protein per h respectively. V max values for patients with CAIS were significantly (P < 0·001) lower than normal subjects. This suggests that aromatase expression in genital skin fibroblasts is androgen-dependent.

Journal of Endocrinology (1990) 127, 177–183

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B A J Evans, K Griffiths and M S Morton

Abstract

Isoflavonoids and lignans, constituents of many plant foods, have been proposed as protective agents in those populations with a low incidence of hormone-dependent cancers. They may act by their inhibition of the metabolism of growth-promoting steroid hormones. This report describes the inhibition of 5α-reductase and 17β-hydroxysteroid dehydrogenase by six isoflavonoids and two lignans in human genital skin fibroblast monolayers and homogenates, and in benign prostatic hyperplasia tissue homogenates. In genital skin fibroblasts, genistein, biochanin A and equol were the most potent inhibitors of 5α-reductase activity, each resulting in greater than 80% inhibition at a concentration of 100 μm. The IC50 values for genistein and a seven-compound mixture were approximately 35 μm and 20 μm (2·9 μm of each compound) respectively. Of the lignans, enterolactone was the most potent inhibitor. Inhibition by biochanin A was shown to be reversible. When genital skin fibroblast homogenates were used, biochanin A was found to inhibit 5α-reductase isozymes 1 and 2 to differing extents (30% and 75% respectively). Genistein was shown to inhibit 5α-reductase 2 in a non-competitive nature (Vmax and Km values without and with inhibitor were 30 and 20 pmol/mg protein per h and 177 and 170 nm respectively). All of the compounds tested inhibited 17β-hydroxysteroid dehydrogenase activity in genital skin fibroblast monolayers. When prostate tissue homogenates were used, the compounds tested were better inhibitors of 5α-reductase 1 than 2. It is possible that a life-long dietary exposure to these lignans and isoflavonoids may have a significant influence on the development of hormone-dependent tumours.

Journal of Endocrinology (1995) 147, 295–302