Examining in vivo effects of silychristin, a potent in vitro inhibitor of thyroid hormone transporter MCT8.

Abstract

Thyroid hormone (TH) availability is particularly critical for early brain development. TH transport across the blood-brain barrier is facilitated through two main transmembrane transporters: monocarboxylate transporter 8 (MCT8) and organic anion transporter 1C1 (OATP1C1). Inhibition of MCT8-mediated TH transport has been identified for a number of environmental chemicals using in vitro screening assays. Here we examined the in vivo effects of exposure to a potent in vitro inhibitor of MCT8, the flavonolignan silychristin, on several aspects of the TH system. Adult female rats were daily gavaged with 0, 250, or 500 mg/kg/day (n = 10/group) of silychristin for 7 days and euthanized on day 8. A smaller group (n = 5/group) of rats was administered the related flavonolignan, silybin (900 mg/kg), or the milk-thistle-derived flavonolignan mixture, silymarin (1,500 mg/kg). Serum TH concentrations were not changed in any treatment group. Mct8 and Oatp1c1 expression were upregulated in the choroid plexus upon silymarin exposure, without change in response to silychristin or silybin. Deiodinase 1 and dehalogenase activities, unchanged in the liver, were increased in the thyroid by the high dose of silychristin. These changes may have been triggered by increased thyroidal TH content, consequent to a reduction in MCT8-mediated TH efflux. Pharmacokinetic properties of silychristin and other flavonoids result in their low bioavailability and likely contributed to the largely negative findings. These observations demonstrate the challenges in extrapolating results from in vitro models to studies in intact organisms, showcasing the importance of selecting appropriate animal models and the best experimental design for assessing effects on human health.