Abstract
Inhibitory effects of flavonoid phytochemicals, flavones, flavonols and isoflavones on cortisol production were examined in human adrenal H295R cells stimulated with di-buthylyl cAMP. In addition, the inhibitory effects of these chemicals on the activity of P450scc, 3β-HSD type II (3β-HSD II), P450c17, P450c21 and P45011β, steroidogenic enzymes involved in cortisol biosynthesis, were examined in the same cells. Exposure to 12.5 μM of the flavonoids 6-hydroxyflavone, 4′-hydroxyflavone, apigenin, daidzein, genistein and formononetin significantly decreased cortisol production (by 6.3, 69.6, 47.5, 26.6, 13.8 and 11.3%, respectively), and biochanin A significantly decreased cortisol production (by 47.3%) at a concentration of 25 μM without any significant cytotoxic effects or changes in cell number. Daidzin, the 7-glucoside of daidzein, did not alter cortisol production by H295R cells at concentrations over 10 μg/ml (24 μM). Daidzein-induced reduction of cortisol production by H295R cells was not inhibited by the estrogen receptor antagonist ICI 182,780. The flavonoids 6-hydroxyflavone, daidzein, genistein, biochanin A and formononetin strongly and significantly inhibited microsomal 3β-HSD II activity at concentrations from 1 to 25 μM, and I 50 values were estimated to be 1.3, 2, 1, 0.5 and 2.7 μM, respectively. In addition, these flavonoids significantly inhibited microsomal P450c21 activity at 12.5 and/or 25 μM. In addition, 6-hydroxyflavone inhibited activity of microsomal P450c17 and mitochondrial P45011β at 12.5 and/or 25 μM. Results of Lineweaver–Burk’s plot analysis indicate that daidzein is a competitive inhibitor of the activity of 3β-HSD II and P450c21. K m and V max values of 3β-HSD II for DHEA were estimated to be 6.6 μM and 328 pmol/min mg protein, respectively. K m and V max values of P450c21 for progesterone were estimated to be 2.8 μM and 16 pmol/min mg protein, respectively. K i values of 3β-HSD II and P450c21 for daidzein were estimated to be 2.9 and 33.3 μM, respectively.
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