The thionamide antithyroid drugs were discovered in large part following serendipitous observations by a number of investigators in the 1940s, who found that sulfhydryl-containing compounds were goitrogenic in animals. This prompted Professor Edwin B. Astwood to pioneer the use of these such compounds to treat hyperthyroidism in the early 1940’s, and to develop the more potent and less toxic drugs that are used today. Despite their simple molecular structure and ease of use, many uncertainties remain, including their mechanism(s) of action, clinical role, optimal use in pregnancy, and the prediction and prevention of rare but potentially life-threatening adverse reactions. In this review, we summarize the history of the development of these drugs, and outline their current role in the clinical management of patients with hyperthyroidism.
Henry Burch and David Cooper
Mohamed A Atwa, Robert C Smallridge, Henry B Burch, Irene D Gist, Rui Lu, Ekbal M Abo-Hashem, Mohamed H El-Kannishy and Kenneth D Burman
Atwa MA, Smallridge RC, Burch HB, Gist ID, Lu R, Abo-Hashem EM, El-Kannishy MH, Burman KD. Immunoglobulins from Graves' disease patients stimulate phospholipase A2 and C systems in FRTL-5 and human thyroid cells. Eur J Endocrinol 1996;135:322–7. ISSN 0804–4643
We have studied the effects of immunoglobulin G from Graves' disease patients on phospholipase A2 (PLA2) and C (PLC) systems in FRTL-5 and human thyroid cells. Immunoglobulin G (IgG) from Graves' disease patients stimulated arachidonic acid (AA) release in a time- and dose-dependent manner. In FRTL-5 thyroid cells, removal of external calcium had no significant effect on the IgG (20 μg/ml)-induced AA release in FRTL-5 thyroid cells. U-73122 (3 μmol/l), a PLC inhibitor, and quinacrine (100 μmol/l) but not U-26384 (5 μmol/l), PLA2 inhibitors, blocked the IgG-induced (20 μg/ml) AA release in FRTL-5 thyroid cells. Immunoglobulin G (100 μg/ml) also stimulated accumulation of inositol-1,4,5-triphosphate (IP3) in a time- and dose-dependent (20–300 μg/ml) manner in FRTL-5 cells. Immunoglobulin G from Graves' disease patients induced a significant increase of IP3 production (p = 0.01) compared to IgG from normal subjects. Removal of external calcium had no significant effect on the IgG-induced IP3 production. The PLC inhibitor U-73122 completely blocked IgG-induced IP3 production from FRTL-5 thyroid cells. Also, in human thyroid cells, IgG from Graves' disease patients induced a significant increase of AA release (p = 0.001) and IP3 production (p = 0.004) compared to the IgG from normal subjects. These data indicate that IgG from Graves' disease patients induced PLA2 activity that was PLC dependent, a pattern referred to as sequential activation. Our studies suggest that IgG from Graves' disease patients activates PLA2 and PLC systems in FRTL-5 and human thyroid cells. These signal transduction pathways could be involved in the pathogenesis of Graves' disease and future studies are warranted to investigate this area.
Kenneth D Burman, Endocrine Section, Washington Hospital Center, 110 Irving St. NW, Washington, DC 20010, USA