The flavonoid Xanthohumol interferes with the thyroid hormone axis

Xanthohumol (XN) is the major prenylated flavonoid of the female inflorescences (cones) of the hop plant (Humulus lupulus). It is also a constituent of beer, a major dietary source of prenylated flavonoids, known to interfere with the sex steroid axis. In the present study, we analyzed in vitro and in vivo effects of XN on thyroid hormone transport and metabolism.

Among the serum thyroid hormone binding and distribution proteins we previously showed a potent and selective competition of XN for T4 binding to transthyretin (TTR) in human and rat serum (IC50=1µM). Using nondenaturing PAGE and OptiQuant phosphoimager we now analyzed interference with human cerebrospinal fluid (CSF) binding of 125I-labeled L-T4 in the absence or presence of increasing concentrations of XN. XN also competed with [125I] T4 binding to TTR in human CSF, thereby increasing the free [125I] T4 fraction. We performed the same assay with serum samples obtained from female ovariectomized rats, treated with different doses of XN for 4 weeks per os or for 2 weeks subcutaneously (n=6 rats in each group). A gradual, dose dependent shift of [125I]-T4 from TTR to albumin and even to thyroxine-binding globulin (TBG) at high doses, was observed. Whether the T4 binding site of TTR is occupied by XN or its metabolite(s) remain to be determined. Preliminary RT- PCR results indicate increased TBG mRNA expression in the liver of rats treated with 250mg/kg BW of XN. Hepatic 5'DI activity in XN treated rats was slightly but not significantly increased compared to control animals (16 vs. 13 pmol iodide released/mg/min).

This study revealed the flavonoid Xanthohumol as a potent competitor for T4 binding to TTR in serum and CSF. Trends toward increased hepatic TBG expression (which is not a major thyroid hormone binding protein in healthy adult rodents) and elevated 5'DI activity in the liver could be a protective mechanism to maintain thyroid hormone homeostasis.

Supported by DFG-grant.