Isoflavonoid-based bone-sparing treatments exert a low activity on reproductive organs and on hepatic metabolism of estradiol in ovariectomized rats

• Published in: Toxicology and applied pharmacology 2007-10, Vol.224 (2), p.105-115
• Main Authors: Phrakonkham, Pascal, Chevalier, Joëlle, Desmetz, Catherine, Pinnert, Marie-France, Bergès, Raymond, Jover, Emmanuel, Davicco, Marie-Jeanne, Bennetau-Pelissero, Catherine, Coxam, Véronique, Artur, Yves, Canivenc-Lavier, Marie-Chantal
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; ANTIGENS; Biological and medical sciences; Bone Density - drug effects; CELL PROLIFERATION; Chemical and Process Engineering; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; DIET; Disease Models, Animal; Engineering Sciences; Equol; ESTRADIOL; Estradiol - metabolism; Estrogen receptors; Female; Food engineering; Gene Expression Regulation - drug effects; Genistein - adverse effects; Genistein - pharmacology; HYDROXYLATION; Isoflavones - adverse effects; Isoflavones - pharmacology; Life Sciences; LIVER; Medical sciences; MENOPAUSE; Menopause - drug effects; METABOLISM; MICROSOMES; Microsomes, Liver - metabolism; NEOPLASMS; Organ Size - drug effects; Osteoporosis - drug therapy; Ovariectomy; OXIDATION; Phytoestrogens - adverse effects; Phytoestrogens - pharmacology; Proliferating Cell Nuclear Antigen - metabolism; RATS; Rats, Wistar; RECEPTORS; SIDE EFFECTS; SKELETON; Soy isoflavone; THERAPY; Toxicology; Uterotrophy; UTERUS; Uterus - drug effects; Uterus - metabolism; Vagina - drug effects; Vagina - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.06.012

The use of soy isoflavones is a potential alternative to hormone replacement therapy in post-menopausal bone-loss prevention. Nevertheless, phytoestrogens can target other organs and may disrupt cell proliferation, or could modify endogenous steroid hormone metabolism. These mechanisms could be linked to an increased risk of developing cancer. We therefore studied the possible side effects of such treatments in an experimental model of menopause. Forty adult female Wistar rats were ovariectomized and fed with a genistein-, daidzein- or equol-supplemented diet at bone-sparing levels (10 mg/kg BW/day) for 3 months. The estrogenic effects were assessed by histological and molecular analyses on reproductive organs. The impact on the oxidative metabolism of estradiol and on associated cytochrome P450 (CYP) activities was evaluated in liver microsomes. The relative wet weights of both the uterus and the vagina were increased in the equol group, but no significant changes in proliferating cell nuclear antigen or hormone receptor mRNA expression were noticed. In contrast, genistein and daidzein did not induce uterotrophy but caused an overexpression of estrogen receptor α mRNA which could correspond to a long-lasting effect of physiological concentrations of estrogens. The hepatic metabolism of estradiol was influenced by daidzein which increased the synthesis of putative mutagenic derivatives. At the same time, genistein favored estrogen 2-hydroxylation, and equol decreased 4-hydroxyestrogen production. Surprisingly, no significant alteration in hepatic CYP activities was detected. Taken together, these results demonstrate that isoflavonoid-based bone-sparing treatments are able to cause side effects on other estrogen-sensitive target organs when given in the long-term.