Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect

Biological effects of genistein are currently under investigation by the National Toxicology Program because of widespread and increasing soy consumption by humans and evidence for modulation of endocrine function. Rats were exposed to genistein aglycone in soy-free feed fortified at 0, 5, 100, and 500 ppm starting in utero through 20 weeks. Thyroid glands and serum were analyzed for total genistein (aglycone + conjugates) using HPLC with electrospray mass spectrometric detection. Microsomal thyroid peroxidase (TPO) activity was measured spectrophotometrically. The total genistein content in rat serum was as high as 8 microM, and significant dose-dependent increases of genistein in thyroid tissue up to 1 pmol/mg were found in male and female rats. The activity of TPO in male and female rats was found to be reduced by up to 80% in a dose-dependent manner. Male and female rats consuming a standard soy-based rodent diet (NIH 31) had TPO activity approximately 50% lower than rats consuming a soy-free diet and this loss was commensurate with measured serum levels of isoflavones. Suicide inactivation of rat, porcine, and human TPO was observed in vitro at concentrations of genistein aglycone comparable to those measured in rat thyroids. Thyroid hormone levels (T3, T4, TSH) in serum, thyroid weights, and histopathology showed no differences between treated and untreated groups. These findings suggest that, even though substantial amounts of TPO activity are lost concomitant to soy isoflavone consumption by normal rats, the remaining enzymatic activity is sufficient to maintain thyroid homeostasis in the absence of additional perturbations.