Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8

Abstract

Thyroid hormones (THs) are charged and iodinated amino acid derivatives that need to pass the cell membrane facilitated by thyroid hormone transmembrane transporters (THTT) to exert their biological function. The importance of functional THTT is affirmed by the devastating effects of mutations in the human monocarboxylate transporter (MCT) 8, leading to a severe form of psychomotor retardation. Modulation of THTT function by pharmacological or environmental compounds might disturb TH action on a tissue-specific level. Therefore, it is important to identify compounds with relevant environmental exposure and THTT-modulating activity. Based on a nonradioactive TH uptake assay, we performed a screening of 13 chemicals, suspicious for TH receptor interaction, to test their potential effects on THTT in MCT8-overexpressing MDCK1-cells. We identified silymarin, an extract of the milk thistle, to be a potent inhibitor of T3 uptake by MCT8. Because silymarin is a complex mixture of flavonolignan substances, we further tested its individual components and identified silychristin as the most effective one with an IC50 of approximately 100 nM. The measured IC50 value is at least 1 order of magnitude below those of other known THTT inhibitors. This finding was confirmed by T3 uptake in primary murine astrocytes expressing endogenous Mct8 but not in MCT10-overexpressing MDCK1-cells, indicating a remarkable specificity of the inhibitor toward MCT8. Because silymarin is a frequently used adjuvant therapeutic for hepatitis C infection and chronic liver disease, our observations raise questions regarding its safety with respect to unwanted effects on the TH axis.

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…Of the TKIs tested, dasatinib was selectively cytotoxic to HPV+, but not HPV-HNSCC cell lines (Supplementary Figure S2), suggesting that it could be used as a treatment for HPV+ HNSCC that expresses high levels of SLC16A2. A flavonoid, silychristin, also inhibits SLC16A2 [45], but has not been studied in cancer models. Other antithyroid hormones used to treat hyperthyroidism, such as carbimazole, methimazole, and potassium perchlorate, could preferentially inhibit HPV+ HNSCC by mimicking inhibition of the SLC16A2 transporter.…”

The Remarkable Effect of Halogen Substitution on the Membrane Transport of Fluorescent Molecules in Living Cells

“…[16] When the cellular uptake of compound 15 was carried out in HepG2 cells,s ilychristin strongly inhibited the uptake in ad ose-dependent manner with an IC 50 value of 8.13 mm,confirming that MCT8 is involved in the transport of the halogen-substituted fluorescent molecules. [16] When the cellular uptake of compound 15 was carried out in HepG2 cells,s ilychristin strongly inhibited the uptake in ad ose-dependent manner with an IC 50 value of 8.13 mm,confirming that MCT8 is involved in the transport of the halogen-substituted fluorescent molecules.…”

“…It has been shown by Johannes et al that silychristin, af lavonolignan derived from the milk thistle,i sapotent inhibitor of MCT8. [16] When the cellular uptake of compound 15 was carried out in HepG2 cells,s ilychristin strongly inhibited the uptake in ad ose-dependent manner with an IC 50 value of 8.13 mm,confirming that MCT8 is involved in the transport of the halogen-substituted fluorescent molecules. An almost complete inhibition of cellular uptake was observed at higher concentrations of silychristin ( Figure 4D and the Supporting Information, Figure S56), which indicates that transporters other than MCT8 are probably not involved in the transport and the introduction of heavier halogen atoms may increase the selectivity of transport through abiological membrane.The inhibition of membrane transport of compound 15 by silychristin was also observed in HeLa and HEK293 cells (Supporting Information, Figures S57 and S58).…”

A Single Atom Change Facilitates the Membrane Transport of Green Fluorescent Proteins in Mammalian Cells

“…The 2‐iodoanisole moiety serves as an efficient receptor recognition unit for compounds 1 – 5 as the iodine atoms can form halogen bonds with the receptor, facilitating their cellular entry . As the GFPs, particularly iodo‐GFP which has the ability to form halogen bonds with the receptor, may enter the cells through MCT8, we studied the cellular uptake in the presence of silychristin (SY), which is a potent and selective inhibitor of MCT8‐mediated uptake . Interestingly, no inhibition of cellular uptake was observed in the presence of SY (Figure A,B), indicating that MCT8 is a specific small‐molecule transporter and it does not mediate the uptake of proteins such as GFP even when they contain iodine atoms.…”