Effect Of MMI Research Articles

NMR structure of an antisense DNA.RNA hybrid duplex containing a 3'-CH(2)N(CH(3))-O-5' or an MMI backbone linker.

The solution structure of an antisense DNA.RNA hybrid duplex, d(CGCGTT-MMI-TTGCGC).r(GCGCAAAACGCG) (designated R4), containing an MMI backbone linker [3'-CH(2)N(CH(3))-O5'], is elucidated. The structural details of the MMI linker, its structural effects on the neighboring residues, and the molecular basis of the MMI effects are examined. The lipophilic N-methyl group of MMI is peripheral to the helix, assuming a conformation that is most stable with regard to the N-O torsion angle. The MMI linker promotes a 3'-endo conformation for the sugar moieties at both 3'- and 5'-adjacent positions and a backbone kink involving distant residues along the 3'-direction. Comparison of R4 with other analogous hybrid duplexes previously studied in this laboratory reveals a new family of low-energy helical conformations that can be accommodated in stable duplexes and a common feature of C3'-modified sugars for adopting a C3'-endo pucker. The results of these studies emphasize the interplay of several factors that govern the formation of stable hybrid duplexes and provide a basis for the understanding of the biological role of the MMI modifications, which are important building blocks for a family of promising chimeric antisense oligonucleotides.

Inhibition of gastric mucosal prostaglandin synthetase activity by mercaptomethylimidazole, an inducer of gastric acid secretion—plausible involvement of endogenous H 2O 2

We have reported earlier that mercaptomethylimidazole (MMI), an antithyroid drug of thionamide group, induces gastric acid secretion at least partially through the liberation of histamine, sensitive to cimetidine. Now, we show that the drug has a significant inhibitory effect on the cyclooxygenase and peroxidase activity of the prostaglandin (PG) synthetase of the gastric mucosal microsomal preparation. The effect can also be mimicked by low concentrations of H 2O 2. While studying the possible intracellular effect of MMI on acid secretion, a cell fraction (F 3) enriched in parietal cell was isolated by controlled digestion of the mucosa with protease. This cell fraction is activated by MMI as measured by increased O 2 consumption. The activation is sensitive to omeprazole, a proton-pump inhibitor, indicating that the activation is due to increased acid secretion by MMI. MMI was also found to directly inhibit the peroxidase activity of the F 3 cell fraction and may thus increase the intracellular level of H 2O 2. The cyclooxygenase activity of the PG synthetase of the F 3 cell fraction is also inhibited by MMI and the effect can be reproduced by low concentrations of H 2O 2. Both MMI and H 2O 2 can also inhibit the peroxidase activity of the PG synthetase. We suggest that in addition to the activation of the parietal cell by MMI possibly through endogenous H 2O 2, MMI induces acid secretion in vivo by inactivating the PG synthetase thereby inhibiting the biosynthesis of PG and removing its inhibitory influence on acid secretion so that the histamine released by MMI can stimulate acid secretion with maximum efficiency.

Inhibition of myo-inositol transport causes acute renal failure with selective medullary injury in the rat

Myo-inositol is a major compatible osmolyte in the renal medulla that is accumulated under hypertonic conditions via the Na+/myo-inositol cotransporter (SMIT). We have recently reported that SMIT is predominantly present in the thick ascending limb of Henle (TAL) and is strongly induced by acute NaCl loading, suggesting an important role of myo-inositol in this nephron segment. In the present study, we sought to examine in vivo effects of inhibition of myo-inositol transport using a transport inhibitor, 2-O, C-methylene-myo-inositol (MMI). Intraperitoneal injection of MMI caused acute renal failure in the rats. Serum creatinine and urea nitrogen were significantly increased 12 hours after MMI injection. Morphologic study revealed that the tubular cells were extensively injured in the outer medulla. A considerable number of the tubular cells were injured in the cortex as well. Immunohistochemical study for Tamm-Horsfall protein (THP), which was used for identification of the TAL cells, showed that THP-positive cells were predominantly injured. The tubular injury apparently appeared to worsen when high concentration of NaCl was injected with MMI. Administration of myo-inositol prevented acute renal failure and improved the tubular injury after MMI injection. Furthermore, supplementation of betaine, another osmolyte in the TAL cells, partially prevented the toxic effects of MMI. These results suggest that myo-inositol play a crucial role in the TAL regarding osmoregulation of the cells.

Hypothyroidism inhibits experimentally-induced acute T cell dependent hepatic damage in mice

In FRTL-5 cells, methimazole (MMI) and propylthiouracil (PTU), both thyroid peroxidase (TPO) inhibitors, increase thyroglobulin (Tg) mRNA levels and Tg accumulation in the medium. An increase in Tg mRNA levels and in Tg accumulation was observed after 2–4 h and 8 h incubation with 10,000 μM MMI or PTU, respectively. Glutamate dehydrogenase mRNA levels, which corresponded with total RNA levels, were not affected. The concentrations of these drugs at which stimulation occurs are higher than the concentrations required for complete inhibition of TPO activity. The stimulatory effects of MMI and PTU can be suppressed by iodide and do not occur when protein synthesis is inhibited by cycloheximide. The effect of MMI on Tg gene expression is not dependent on thyrotropin (TSH) or insulin and MMI does not change the TSH-induced cAMP production. We conclude that MMI and PTU interfere in a regulatory pathway for Tg gene expression.

Effect of orally administered antithyroid thioureylenes on PCNA and P53 expression in psoriatic lesions.

Antithyroid thioureylenes are effective agents in the oral and topical treatment of patients with chronic plaque psoriasis. The effect of oral treatment with 6-n-propyl 2-thiouracil (propylthiouracil, PTU) and 2-mercapto 1-methyl imidazole (methimazole, MMI) on proliferating cell nuclear antigen (PCNA), and p53 protein expression was studied in patients with stable plaque psoriasis. Following treatment with PTU and MMI, PCNA staining in psoriatic epidermis was significantly decreased. P53 was minimally expressed in untreated lesions, and treatment with PTU and MMI did not enhance p53 expression in the psoriatic lesions. Since PCNA is a marker of cellular proliferation and p53 inhibits cellular cycling, some of the beneficial effects of PTU and MMI in psoriasis may depend on the ability of the drugs to impair cellular turnover, perhaps by binding to the triiodothyronine (T3) receptor. These effects may be in addition to the previously described effects of PTU and MMI as immune modulators and free radical scavengers.

The effects of methimazole on haematopoiesis in mice.

The effects of anti-thyroid drug, methimazole (MMI), on haematopoiesis in inbred C57BL/6 mice were studied. The in vitro proliferative response of bone marrow (BM) cells to interleukin-3 (IL-3) was significantly increased when mice were provided with 0.1% MMI in water (w/v) ad librium for 4 to 6 weeks. Using soft agar agar colony assay, the numbers of myeloid cell colonies were also significantly increased in mice treated with MMI. However, the proliferative response of BM cells to IL-3 was found to be greatly reduced 10 weeks after MMI treatment. In vitro studies showed that MMI alone at the concentrations of 500 microM or above inhibited both the growth of normal BM cells in liquid culture and the formation of macrophage (M)-/granulocyte (G)-colonies in soft agar culture in a dose dependent manner. Direct cytotoxic effect of MMI (0 - 1250 microM) to normal BM cells was not observed. Results from this study suggested that MMI can modulate the development of myeloid haematopoietic cells.

Methimazole inhibits FRTL5 thyroid cell proliferation by inducing S-phase arrest of the cell cycle.

Previous studies, using tritiated thymidine uptake assays, had indicated a nil or stimulatory effect of methimazole (MMI) on thyroid cell proliferation. Whilst examining cell cycle kinetics of FRTL5 thyrocytes, we observed an inhibitory effect of MMI on thyroid cell proliferation. To further examine this observation, FRTL5 cells whilst in log phase proliferation were exposed to media containing either 6H or MMI in 6H. Cell number and cell cycle kinetics were examined using flow cytometric DNA analysis every 24 hrs for 96 hrs. We found that MMI inhibited cell proliferation (as assessed by cell number) throughout the experimental period. Cell cycle analysis revealed a persistent arrest of cells in S phase. Concomitantly, there was a fall in the proportion of cells in both G0G1 and G2M phases, in keeping with cell cycle arrest in S phase. Taken in isolation, the finding of a high proportion of cells in S phase would suggest stimulation of cell proliferation, consistent with the findings of previous studies which used tritiated thymidine uptake assays to assess cell proliferation. However, the absence of a concomitant increase in total cell number renders this argument invalid and argues for a specific effect of MMI on the cell cycle. This study demonstrates a hitherto unrecognised inhibitory action of MMI on FRTL5 thyroid cell proliferation which has implications in understanding the broader effects of MMI on thyroid cell physiology. Additionally, this study highlights the dangers of using tritiated thymidine uptake measures as the sole indicator of mitogenic activity.

Differential effects of methimazole and dexamethasone in avian muscular dystrophy

We showed previously that thyroid antagonists and glucocorticoids partially alleviated the impaired righting ability and abnormally high levels of plasma creatine kinase activity in genetically dystrophic chicks. The goals of the present study were: (1) to ascertain whether the beneficial effects of methimazole (MMI; thyroid antagonist) on muscle function and plasma creatine kinase (CK) activity in dystrophic thickens are correlated with significant reduction in plasma triiodothyronine (T3) and thyroxine (T4); (2) to assess whether the MMI-induced thyroid changes are accompanied by increased plasma corticosterone level and/or changes in muscle glucocorticoid receptors which might account partially for the beneficial effects of MMI; and (3) to determine if plasma T3 and T4 are reduced in dexamethasone (DEX) treated dystrophic chickens which might account at least partially for the beneficial effects of DEX (a potent glucocorticoid) on avian dystrophy. The data show that beneficial effects of MMI are associated with reduced plasma levels of thyroid hormones and increased circulating levels of corticosterone. In addition, DEX actually increases plasma T3 levels. these differential effects indicate that reduced plasma thyroid hormone levels do not represent a common mechanism of beneficial drug effects in avian muscular dystrophy. On the other hand, elevated plasma glucocorticoid levels accompany the beneficial effects of both severe hypothyroidism and DEX treatment. The data also show that MMI induces down-regulation of muscle cytosolic glucocorticoid receptors which are higher than normal in dystrophic muscles.

Transforming growth factor-beta 1 production in porcine thyroid follicular cells: regulation by intrathyroidal organic iodine.

The present studies have demonstrated the production of transforming growth factor-beta 1 (TGF-beta 1) by porcine thyroid follicular cells (TFCs) maintained in vitro as subconfluent monolayers, and have confirmed a stimulatory effect of iodide on thyroidal TGF-beta 1 mRNA and peptide release. RNA extracted from TFCs maintained in the absence of iodide contained a 2.5 kb transcript which hybridized specifically with a cDNA probe for human TGF-beta 1, and which showed an approximate doubling in intensity in cells exposed to 10 mumol NaI/1. In the presence of the anti-thyroid thionamide drug methimazole (MMI; 1 mmol/l), the action of iodide on TGF-beta 1 mRNA was attenuated, although MMI alone had no effect on the control level of TGF-beta 1 mRNA. The TGF-beta 1 peptide content of TFC-conditioned media (TFC-CM) was assessed using the fetal mink lung cell line Mv1Lu, in which activated TGF-beta 1 specifically suppresses trichloroacetic acid-precipitable [methyl-3H]thymidine incorporation. Newly conditioned TFC-CM stimulated [methyl-3H]thymidine incorporation into Mv1Lu cells, but after heat treatment to inactivate growth stimulators and activate the latent TGF-beta 1 component this medium inhibited [methyl-3H]thymidine incorporation. This inhibitory effect was prevented by immunoadsorption of TFC-CM with a TGF-beta 1-neutralizing antiserum, confirming the specificity of the inhibitory response. The inhibitory activity of TFC-CM was increased when the TFCs were preincubated with 10 mumol NaI/1, and lost when TFCs were exposed to MMI. In conclusion, TFCs produce TGF-beta 1 mRNA and TGF-beta 1 peptide, which are both increased by iodide treatment in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Methimazole and propylthiouracil increase thyroglobulin gene expression in FRTL-5 cells

In FRTL-5 cells, methimazole (MMI) and propylthiouracil (PTU), both thyroid peroxidase (TPO) inhibitors, increase thyroglobulin (Tg) mRNA levels and Tg accumulation in the medium. An increase in Tg mRNA levels and in Tg accumulation was observed after 2–4 h and 8 h incubation with 10,000 μM MMI or PTU, respectively. Glutamate dehydrogenase mRNA levels, which corresponded with total RNA levels, were not affected. The concentrations of these drugs at which stimulation occurs are higher than the concentrations required for complete inhibition of TPO activity. The stimulatory effects of MMI and PTU can be suppressed by iodide and do not occur when protein synthesis is inhibited by cycloheximide. The effect of MMI on Tg gene expression is not dependent on thyrotropin (TSH) or insulin and MMI does not change the TSH-induced cAMP production. We conclude that MMI and PTU interfere in a regulatory pathway for Tg gene expression.

Dissociation of gastric acid and pepsinogen secretion in response to mercaptomethylimidazole—A new secretory compound

Mercaptomethylimidazole (MMI), a potent antithyroid drug of the thionamide group, induces both acid and pepsinogen secretion independently in control and pylorus ligated mice. The effect is dose dependent and the drug is more effective than histamine, carbachol or isoproterenol when administered by an intraperitoneal route. MMI-stimulated pepsinogen secretion could be dissociated from the acid secretion by the use of cimetidine and omeprazole which effectively block the acid secretion without affecting the pepsinogen output. Neither acid nor pepsinogen secretion by MMI is inhibited by atropine indicating a lack of muscarinic receptor involvement in both of the processes. Nifedipine and verapamil, the calcium antagonists, by inhibiting the MMI-induced acid secretion can also dissociate pepsinogen secretion from the acid secretion. Clonidine, an α 2-agonist, and hexabarbital, a membrane active barbiturate, also inhibit acid secretion without affecting the pepsinogen output. These data indicate that MMI induces pepsinogen secretion independent of acid secretion. Furthermore, MMI-stimulated acid secretion is not additive with that of the histamine indicating same site (H 2-receptor) of action while its synergistic effect in presence of carbachol (muscarinic receptor) indicates different site of interaction of the two compounds. On the other hand, an additive effect of MMI and carbachol on pepsinogen secretion indicates that while the carbachol effect is mediated through the muscarinic receptor, MMI stimulates pepsinogen secretion through some still unknown mechanism.

The effect of methimazole on the immune system is unlikely to operate directly on T lymphocytes

It has been shown that the antithyroid drug methimazole (MMI) may affect B cells and possibly accessory cell function. In the present study we investigated in detail the effects of MMI on T cell in vitro proliferation. The following variables were evaluated: T cell proliferation following stimulation with phytohemagglutinin (PHA), and anti-CD3 or anti-CD2 monoclonal antibodies; interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) production by PHA-stimulated T cells in bulk culture and by T cell clones; PHA-induced IL-2 receptor expression; LPS-induced interleukin-1 production by accessory cells. The results obtained failed to demonstrate any effect of MMI on T cells in vitro proliferation, whatever the activation pathway considered. In addition, IL-2 and gamma-IFN productions were substantially unaffected by the drug, as well as IL-1 production by accessory cells. However, a slight reduction of PHA-induced IL-2 receptor expression was observed. Although the hypothesis of an effect of MMI on some specialized T cell functions cannot be ruled out, it is likely that the supposed "immunosuppressive" effect of the drug does not concern primarily the T lymphocyte.

Thionamides and arsenite inhibit specific T3 binding to the hepatic nuclear receptor

Methimazole (MMI) and propylthiouracil (PTU) are widely used for the treatment of Graves' disease. However, no studies have been reported on the action of these drugs on binding of L-triiodothyronine (T3) to the nuclear receptor. T3 receptors of rat liver nuclei, prepared by differential centrifugation, were extracted with 0.4 M KCl and 5 mM dithiothreitol (DTT). In the assessment of T3 binding to the DTT-reduced receptor, the hepatic nuclear extract was chromatographed on Superose 6 to remove DTT and isolate proteins of relative mass approximately 50,000 (chromatographed nuclear receptors (CNRs)), prior to the addition of [125I]T3 of high specific activity (3300 microCi/micrograms; 1 Ci = 37 GBq). MMI or PTU at 2 mM reduced specific T3 binding to CNR by 84% and 85%, respectively. The inhibitory effects of these reagents and 2 mM sodium arsenite (which complexes dithiols) were additive. Scatchard analyses indicated that neither MMI nor PTU (at 2 mM) significantly altered the affinity constant (Ka) (from 2.41 x 10(9) to 1.74 x 10(9) M-1 for PTU and 1.79 x 10(9) M-1 for MMI), while they both decreased (p less than 0.02) maximal binding capacity (from 0.36 +/- 0.02 to 0.19 +/- 0.02 pmol/mg protein for MMI and 0.17 +/- 0.02 pmol/mg protein for PTU). Dose-response curves showed that 50% inhibition was attained at 0.6 mM PTU or 1.0 mM MMI with approximately 25% inhibition by both at 0.1 mM. Artefactual binding effects by MMI and PTU on [125I]T3 were excluded by chromatography experiments. Similar results were obtained using nuclear receptors prepared from livers of hyperthyroid rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibitory effect of large doses of methimazole on iodine induced lymphocytic thyroiditis and serum anti-thyroglobulin antibody titers in BB/Wor rats.

The BB/Wor rat spontaneously develops autoimmune insulin dependent diabetes mellitus and lymphocytic thyroiditis (LT). Excess iodine ingestion enhances and low iodine diet decreases the incidence of LT in this rat model but does not affect the incidence of diabetes mellitus. The administration of a low dose of methimazole (MMI; 870 ng/gm bw ip daily) from 30-90 days of age had no significant effect on thyroid function or on the incidence of iodine induced LT and serum anti-thyroglobulin (Tg) antibodies measured by an ELISA assay. A large dose of MMI (0.05% in the drinking water) induced goiter and hypothyroidism. In addition, the incidence of LT was markedly attenuated (76% vs 6%, p less than 0.001) and reduced titers of serum anti-Tg antibodies (0.59 +/- 0.1 OD vs 0.08 +/- 0.01, p less than 0.001) were observed. This inhibitory effect of MMI on the occurrence of iodine induced LT in the BB/Wor rat may be due to the lower antigenicity of the poorly iodinated Tg secondary to MMI therapy and/or to an immunosuppressant effect of MMI itself.

The Study of Direct Effect of Methimazole on Thymidine Incorporation in FRTL-5 Cells

During the course of treatment of Graves' disease with the anti-thyroid drug, methimazole (MMI), a decrease in a patient's goiter size is sometimes observed. Using rat thyroid cell strain, FRTL-5, the direct effect of MMI on thyroid cell growth was investigated. FRTL-5 cells (2 X 10(5)) were cultured for 48 hours with TSH, (Bu)2 cAMP or forskolin in the presence of [3H]-thymidine. All three stimulators increased cell growth, expressed as [3H]-thymidine incorporation into DNA in a dose-dependent fashion. When FRTL-5 cells were cultured for 48 hours in the presence of MMI at 10(-6)-10(-3) M with these stimulators (TSH 250 microU/ml, (Bu)2 cAMP 10(-3) M, forskolin 10(-5) M), [3H]-thymidine incorporation was suppressed in dose-dependent fashions (MMI 10(-5) M-10(-3) M). From the present study, it is suggested that methimazole directly modulates thyroid cell growth induced by thyroid growth stimulators which are involved in adenylate cyclase-cyclic AMP system and that the site of its action exists beyond cAMP production.

Duration of antithyroid action of methimazole estimated with an intravenous perchlorate discharge test.

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30-min uptake (mean +/- SD), was 81.7 +/- 3.3% at 2.2 h, 69.3 +/- 18.9% at 5.9 h, 22.6-23.4% at 13.4 h and 2.7-6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 +/- 1.9% at 2.2 h, 84.3 +/- 8.8% at 6.3 h, 64.8 +/- 24.1% at 13.3 h and 26.9-29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3-6 h and 17-20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

The conversion of thyroxine to triiodothyronine (T3) or to reverse T3 in patients with thyroid dysfunction

In order to clarify the conversion of thyroxine (T4) to triiodothyronine (T3) or to reverse T3 (rT3), serum concentrations of T4, T3, rT3, thyrotropin (TSH), thyroxine-binding globulin (TBG) and values of T3 uptake (T3 U) were measured in 61 hyperthyroid and 31 hypothyroid patients, 8 patients with subacute thyroiditis, and 40 normal subjects. Then, free T4 index (FT4I), T3/T4, rT3/T4, and rT3/T3 ratio were calculated. The rT3/T3 ratio was high in the hyperthyroid patients and low in the hypothyroid patients compared with that in the normal subjects. The ratio was positively related to serum T4, T3, rT3 levels, and FT4I in the patients and normal subjects. The regression equation was represented by rT3/T3 = 0.015[T4] + 0.083. No influences of serum TBG and age on the rT3/T3 ratio were observed. Our results indicated that thyroid hormones themselves could regulate the conversion of T4 to T3 or rT3 by activating 5-monodeiodinase in hyperthyroidism and by activating 5'-monodeiodinase and suppressing 5-monodeiodinase in hypothyroidism. Serum rT3 level was a more sensitive parameter than serum T4 or T3 for evaluating thyroid dysfunction. During the treatment with methimazole (MMI) or L-thyroxine and the natural course of subacute thyroiditis, serum T4 levels and rT3/T3 ratios changed parallel to the regression line. However, once adverse effects of MMI occurred, those changed out of the line. From these results, we concluded that the relationship between serum T4 level and rT3/T3 ratio should be examined for adequate information concerning the peripheral conversion of thyroid hormones under various thyroid diseases.

Methimazole-induced modulation of thiobenzamide bioactivation and toxicity

The formation of thiobenzamide- S-oxide (TBSO) from thiobenzamide (TB) by rat liver microsomes was competitively inhibited by methimazole (MMI; l-methyl-2-mercaptoimidazole), a known substrate and inhibitor of the microsomal FAD-containing monooxygenase. S-oxidation was also temporarily depressed in liver microsomes obtained from MMI-treated rats. When administered in vivo, MMI alleviated TB-induced liver necrosis in a dose-dependent manner; moreover, a significant decrease in the serum concentration of TBSO was observed. The protective effect of MMI against the necrogenic effect of TB could arise from competition of these two chemicals for the same bioactivating system, leading to a lower production of the liver damaging metabolite, TBSO.

Effect of Antithyroid Agents 6-Propyl-2-Thiouracil and l-Methyl-2-Mercaptoimidazole on Human Thyroid Iodide Peroxidase

The mechanism of inhibition of human thyroid iodide peroxidase (TPO) by 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) used in the therapy of hyperthyroid patients was studied in vitro. The inhibition of TPO by MMI was not restored either by dialysis or by dilution, but the inhibition by PTU was restored by both treatments. PTU interacted directly with the product of TPO action (oxidized iodide) in the reaction mixture without significantly affecting TPO activity. MMI interacted directly with TPO and inhibited enzyme activity, rather than interacting with the product (oxidized iodide). The inhibition was irreversible with MMI, but reversible with PTU. The concentrations of PTU and MMI producing 50% inhibition of TPO were 2 x 10-6m and 8 x 10-7m, respectively, 2-Mercaptoimidazole inhibited TPO reversibly but 1-methylimidazole and imidazole did not. Both the methyl and mercaptoresidues in MMI moiety are thought to be essential to its irreversible inhibition of TPO. The in vivo effect of MMI and PTU on TPO activity was also studied. TPO activities in the thyroid homogenate of rats to which MMI (2 mg per rat) or PTU (10 mg per rat) had been administered intraperitoneally were determined before and after dialysis against buffer. TPO activity in the PTU treated thyroid homogenate was significantly lower than that in the control before dialysis, but the activity was restored to the control value after dialysis. On the contrary, TPO activity in the MMI treated thyroid homogenate was significantly lower than that in the control and was not affected by dialysis. These data may explain why MMI is a more potent inhibitor of iodination than PTU and may fit the clinical results observed when hyperthyroid patients are treated with these agents.

Effect of MMI on the serum T3 and T4 levels in hyperthyroid patients (author's transl)

Effect of 1-methyl-2-mercaptoimidazole (MMI) on the serum triiodothyronine (T3) and thyroxine (T4) was studied in six patients with hyperthyroidism. From 30 to 60 mg of MMI per day were administered to the patients orally. Serum T3 was measured by radioimmunoassay and T4 by radioimmunoassay of Tetrasorb Kit (Abbott Lab.). Serum T4/T3 ratios in these patients were low initially, but increased to normal range in two cases immediately after the administration of MMI. But they were unchanged at first in the other four cases. When high serum T3 values decreased abruptly to normal at a later course of medication, the serum T4/T3 ratios increased to normal range in almost all cases. Even though the serum T4/T3 ratio became normal, serum T3 and T4 values remained high in some cases. Elevated serum T4 values in all cases decreased to normal faster than serum T3 with the administration of MMI. When MMI was administered to the patents concinuously, the T4/T3 ratios, once increased to normal, then decreased again gradually in five cases. And serum T3 which decreased to normal sometimes gave high values. After the discontinuation of MMI, serum T3 increased over the normal range more rapidly than did T4.