Genistein Increase Thyroid Hormone and 7 alpha-hydroxycholesterol concentrations in the liver of middle-aged male rats

Abstract

Obesity, a major public health problem, is associated with hypercholesterolemia and other metabolic disorders, which are potent risk factors for athero-thrombotic disease, a leading cause of mortality worldwide. Advances in both dietary and pharmacological interventions contribute significantly to prevention and treatment of modifiable risk factors. Consumption of purified soybean isoflavones was reported to reduce plasma and liver cholesterol levels. The precise mechanism has not been established, but it has been suggested that these effects occur through an increase in bile acid excretion. The initial and rate limiting step in the classical pathway of hepatic synthesis of bile acids from cholesterol is the enzymatic addition of a 7α hydroxyl group by cholesterol 7α-hydroxylase forming 7α-hydroxycholesterol. Thyroid hormones have been shown to up-regulate expression of this enzyme. We previously reported that subcutaneously administered genistein impaired thyroid functioning in middle-aged rats, but at the same time increased expression of T3-activated genes and increased deiodinase type 1 enzyme activity in the liver. In this study we aimed to further determine effects of genistein on concentrations of thyroid hormones, total cholesterol and 7α-Hydroxycholesterol in the liver. Thirteen-month-old male Wistar rats were injected subcutaneously with 35 mg/kg of genistein, while controls received vehicle alone daily during 4 weeks. For determination of iodothyronines liquid chromatography-mass spectrometry was applied, while total cholesterol and 7α-hydroxycholesterol were determined by gas chromatography/mass spectrometry. Our study results clearly demonstrate that genistein increased (P<0.05) concentration of T4 and T3 in the liver of middle-aged male rats. In line with this, concentration of 7α-hydroxycholesterol also increased (P<0.05), but the total cholesterol levels remained unchanged. In conclusion, genistein increased hepatic availability of thyroid hormones, in accordance with detected increase in 7α-hydroxycholesterol level in the liver. The obtained data brought new light on the mechanisms involved in biological processes in the liver induced by genistein.