Article

Phytoestrogens inhibit human 17β-hydroxysteroid dehydrogenase type 5

GSF National Research Center for Environment and Health, Institute for Experimental Genetics, Genome Analysis Center, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
Molecular and Cellular Endocrinology DOI:10.1016/S0303-7207(00)00422-6 pp.151-162

ABSTRACT The 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD 5) is involved in estrogen and androgen metabolism. In our study we tested the influence of environmental hormones, such as phytoestrogens (flavonoids, coumarins, coumestans), on reductive and oxidative 17β-HSD activity of the human 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD 5). These dietary substances were shown to be potent inhibitors of aromatase, different 17β-HSDs and seem to play an important role in delay of development of hormone dependent cancers. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many dietary compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among the group of flavones inhibitor potency is growing with increasing number of hydroxylations. We suggest that these substances are bound to the hydrophilic cofactor-binding pocket of the enzyme. An interesting inhibition pattern is observed for 18β-glycyrrhetinic acid, which has no influence on the oxidative but only on the reductive reaction. This indicates that this substrate binds to pH- and cofactor-depending sites at the active center of the enzyme.

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    Article: Inhibition of extrahepatic human cytochromes P450 1A1 and 1B1 by metabolism of isoflavones found in Trifolium pratense (red clover).
    Dean W Roberts, Daniel R Doerge, Mona I Churchwell, Gonçalo Gamboa da Costa, M Matilde Marques, William H Tolleson
    [show abstract] [hide abstract]
    ABSTRACT: Biochanin A and formononetin are the predominant isoflavones in red clover. In a previous study (J. Agric. Food Chem. 2002, 50, 4783-4790), it was demonstrated that human liver microsomes converted biochanin A and formononetin to genistein and daidzein. This paper now shows CYP1B1-catalyzed O-demethylation of biochanin A and formononetin to produce genistein and daidzein, respectively, which inhibit CYP1B1. Recombinant human CYP1A1 or CYP1B1 was incubated with biochanin A or formononetin. CYP1A1 catalyzed isoflavone 4'-O-demethylation and hydroxylations with similar efficiency, whereas CYP1B1 favored 4'-O-demethylation over hydroxylations. Three of the biochanin A metabolites (5,7,3'-trihydroxy-4'-methoxyisoflavone, 5,7,8-trihydroxy-4'-methoxyisoflavone, and 5,6,7-trihydroxy-4'-methoxyisoflavone) were characterized by 1H NMR spectroscopy and mass spectrometry. Daidzein (Ki = 3.7 microM) exhibited competitive inhibition of CYP1B1 7-ethoxyresorufin O-deethylase activity, and genistein (Ki = 1.9 microM) exhibited mixed inhibition. Biochanin A and/or formononetin may exert anticarcinogenic effects directly by acting as competitive substrates for CYP1B1 or indirectly through their metabolites daidzein and genistein, which inhibit CYP1B1.
    Journal of Agricultural and Food Chemistry 11/2004; 52(21):6623-32. · 2.82 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

17β-hydroxysteroid dehydrogenase type 5
 
18β-glycyrrhetinic acid
 
androgen metabolism
 
biochanin A
 
cofactor-depending sites
 
dietary substances
 
different 17β-HSDs
 
environmental hormones
 
flavones inhibitor potency
 
flavonoids
 
human 17β-hydroxysteroid dehydrogenase type 5
 
hydrophilic cofactor-binding pocket
 
interesting inhibition pattern
 
oxidative
 
oxidative 17β-HSD activity
 
oxidative activity
 
potent inhibitors
 
reductive reaction
 
substrate binds
 
zearalenone