MINOCYCLINE AND THE THYROID - ANTITHYROID EFFECTS OF THE DRUG, AND THE ROLE OF THYROID PEROXIDASE IN MINOCYCLINE-INDUCED BLACK PIGMENTATIONOF THE GLAND

Minocycline (MN), a member of the tetracycline family of antibiotics, is known to induce a black discoloration of the thyroid in several spe cies, including humans. Antithyroid effects of MN have also been repor ted. The aim of the present study was two-fold: (1) to determine wheth er thyroid peroxidase (TPO) is involved in the MN-induced black thyroi d, and (2) to obtain information on the effect of MN on TPO-catalyzed iodination and coupling in model systems containing highly purified TP O. Treatment of MN with TPO in the presence of the H2O2 generating sys tem, glucose-glucose oxidase, resulted in the formation of a black pro duct (or products). In phosphate buffer, pH 7.0, the color intensity r eached its peak in about 90 min. Control samples without TPO showed li ttle or no color change during this interval. Formation of the black p roduct(s) did not require the presence of iodide. Other members of the tetracycline family were not oxidized to dark products by the TPO sys tem. These results provide definitive evidence that TPO is involved in the MN-induced black thyroid. MN is an inhibitor of TPO-catalyzed iod ination in model systems, with a potency comparable to that of MMI and PTU. At low drug concentrations (similar to 25 mu M), MN appeared to act as a competitive inhibitor, as previously shown for lower concentr ations of MMT and PTU. However, when the drug concentration was increa sed, MN and the thioureylene drugs inhibited iodination by different m echanisms. With PTU and MMI, iodination was irreversibly inhibited thr ough inactivation of TPO. However, inhibition of iodination by MN (100 mu M) was not associated with inactivation of TPO and was at least pa rtially reversible. The most potent inhibitory effect of MN was on TPO -catalyzed coupling. This was demonstrated both in a coupling test sys tem, designed to measure coupling in the absence of iodination, and in an iodination system, in which iodination and coupling occurred simul taneously. In both systems, MN was several times more potent than PTU and MMI, or other tetracycline drugs. Based on the potent antithyroid effects of MN observed in our in vitro studies, it seems advisable to monitor thyroid function in patients receiving long-term MN therapy.