One of the reasons silychristin is important is that it is a constituent of Milk Thistle - it is a flavonoid abundant in milk thistle fruits, known for its antioxidant and anti-inflammatory effects, particularly in conditions like hepatitis C infection and chronic liver disease. There is concern over silychristin’s potential adverse effects on thyroid hormone transport.
The importance is that you need to consider the issues if you are, or are considering, taking Milk Thistle or its extracts.
The papers are not easy reads. Definitely a lot of their content beyond my capacity to understand! However, as with so many things, simply being aware just might make all the difference.
Structural insights into thyroid hormone transporter MCT8
Abstract
Thyroid hormones (THs), including T4 (3,5,3′,5′-tetraiodo-L-thyronine) and T3 (3,5,3′-triiodo-L-thyronine), play critical roles in regulating tissue development and basal metabolism. Monocarboxylate transporter 8 (MCT8) is a key player in TH transport, known for its high specificity and affinity for THs and its direct association with Allan-Herndon-Dudley syndrome (AHDS) caused by pathogenic mutations. In this study, we present the cryo-EM structures of human MCT8 bound to the substrate T3 or the inhibitor silychristin, both in an outward-open conformation at resolutions of 3.0-3.2 Å. MCT8 forms a homodimer with a lipid molecule positioned at the dimerization interface. The carboxyl group of T3 is recognized by Arg371, while its three iodine atoms interact with distinct hydrophobic cavities. Silychristin is also recognized by Arg371, competing with T3 for binding. Complemented by structure-guided biochemical analyses, our research elucidates the mechanisms of substrate recognition and transport, as well as the mode of action of the inhibitor silychristin. These findings may offer insights for developing targeted therapies for TH-related disorders.
Open access:
nature.com/articles/s41467-...
The new paper is very largely an explanation of some of the details of the issue that was reported in the paper below - and other sources.
Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8
Jörg Johannes 1 , Roopa Jayarama-Naidu 1 , Franziska Meyer 1 , Eva Katrin Wirth 1 , Ulrich Schweizer 1 , Lutz Schomburg 1 , Josef Köhrle 1 , Kostja Renko 1
Affiliations
PMID: 26910310
DOI: 10.1210/en.2015-1933
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.
A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients
