Endocrine Abstracts (2002) 3 P220

Phytoestrogens as inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 in luteinized human granulosa cells

M Lacey & SA Whitehead

Department of Physiology, St George's Hospital Medical School, London, UK.

Studies on breast cancer cell lines, placental microsomes and purified recombinant enzymes have shown that various phytoestrogens can inhibit both aromatase and 17beta-hydroxysteroid dehydrogenase (HSD) enzymes. This has led to the suggestion that certain phytoestrogens may exert their endocrine disrupting functions by enzyme inhibition rather than their ability to bind weakly to oestrogen receptors. Previous studies have shown that genistein, the active ingredient of soy, induces a potent inhibition of both aromatase and 17beta-HSD type 1 activity in primary cultures of human granulosa luteal (GL) cells. We have extended these studies to investigate the action of several phytoestrogens that have been reported to have relatively potent inhibitory effects on steroidogenic enzymes. GL cells, obtained after written consent from the patients, were cultured for 48h with FCS, for a further 24h in serum-free medium with FSH alone or with FSH + drugs and for a final 4h period with fresh medium, drugs and steroid substrates; namely androstenedione (4-dione), testosterone (T) or oestrone (E1). The production of oestradiol (E2)from different substrates was measured by radioimmunoassay.

Apigenin induced an acute inhibition of aromatase and 17 beta-HSD whilst biochanin A, coumestrol, quercertin and zealarone were without effect. A different profile of responses were observed when GL cells were exposed to the phytoestrogens 24h prior to testing enzyme activity. Coumestrol and quercertin induced inhibition of aromatase activity (p<0.01) but only at the highest dose (10-4M). Biochanin A and zearalone showed a potent dose-dependent inhibition of aromatase activity (p<0.001) but no inhibtion of 17beta-HSD type 1 that converts E1 to E2. Apigenin significantly (p<0.01) inhibited the activity of both enzymes. The relative potency of these five compounds differ from those observed in other studies using different experimental models. The results thus suggest that human GL cells may metabolise the phytoestrogens to more or less active compounds and/or their effects involve transcriptional changes.

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