ROS production induced by 3,5-di-iodo-thyronine: anew nongenomic effect of thyroid hormones

3,5-Diiodo-thyronine (3,5-T2) is a deiodination metaboliteof T3 that has been reported to be able to mimic someimportant rapid nongenomical effects of T3. High levels of3,5-T2 have been found in connection with some types ofbrain tumors and other nonthyroidal illnesses such as livercirrhosis, and it appears that 3,5-T2 may have a specificphysiopathological role. Previous results from our laboratorydemonstrated that 3,5-T2 in the physiological range (around0.1 nM) mimics T3 activation of the Na/H exchanger, causingan increase in the intra-cellular pH of L-6 myoblastsand chick embryo hepatocytes. We here show that 3,5-T2also increases the fluorescence of dicloro-fluorescein in L-6 myoblasts, probably due to production of reactive oxygenspecies (ROS). The increase is partially prevented by extracellularsuperoxide dismutase (SOD) or by treatment of cellswith an inhibitor of the plasma membrane NADPH oxidase,that is believed to be an important source of superoxide formation both inside and outside cells. Experiments with EPRspectroscopy, using Cu,Zn SOD as a probe, show that 3,5-T2over a wide concentration range induces superoxide formation,whereas other analogs of thyroid hormones do not givethe same effect. The results also indicate that super-oxide isproduced on the outside of the cell membrane, probably dueto activation of the membrane NADPH oxidase. Experimentsare in progress in order to establish whether ROS productioninduced by 3,5-T2 represents a physiological signal, possiblyas part of a response to a pathological condition.