In vitro hemmung der histidindecarboxylasen durch antithyreoidale substanzen

Abstract

The specific histidine decarboxylase of the thyroid gland of pigs and of the stomach of rats and the nonspecific histidine decarboxylase of the kidney of guinea pigs are inhibited by inhibitors of intrathyroid hormone synthesis in vitro. m-Fluortyrosine, an inhibitor of iodide ion trapping, and 5-fluoruracil, a cytostatic drug, are ineffective. 2-mercaptobenzimidazole-1,3-dimethylol is a relatively strong inhibitor of the specific and unspecific histidine decarboxylase, 2-carbethoxythio-1-methylimidazole is effective too, but 6-propyl-2-thiouracile and 6-methyl-2-thiouracile are only weak inhibitors. The K m of the unspecific histidine decarboxylase and histidine is 1.7 × 10 −3M, if the velocity of reaction is calculated as initial velocity and not after an incubation time of 3 hr, when values between 10 −2 and 10 −1 M have been reported. Newer results do not agree with the suggestion, that the nonspecific histidine decarboxylase does not play a role in the decarboxylation of histidine in vivo. 2-Mercaptobenzimidazole-1,3-dimethylol inhibits the nonspecific histidine decarboxylase competitively with respect to histidine and pyridoxal phosphate. The K i -values for histidine and pyridoxal phosphate are 1.7 × 10 −4 and 2.7 × 10 −4 M, the K m for pyridoxal phosphate being 6 × 10 −5 M. From this 2-mercaptobenzimidazole-1,3-dimethylol shows a 10-fold higher affinity to the active center of the nonspecific histidine decarboxylase than histidine. During the incubation and complete inhibition of histidine decarboxylase the histamine content in the incubation mixture is diminished though aminoguanidine and chlorpromazine have been added. In the presence of antithyroid drugs, such as 2-carbethoxythio-1-methylimidazole, in concentrations greater than 1 × 10 −3 M, the fluorescence of the condensation product of histamine and o-phthaldialdehyde is diminished. Histamine therefore has been estimated on the isolated guinea pig's ileum, because the substances can be separated from histamine by the extraction procedure only to 50 per cent. The diminishing effect is not caused by quenching, but by reaction of phthaldialdehyde with the inhibitors and partial absorption of the exciting light. This effect can be used for estimation of the antithyroid drugs. An influence of histamine on the intrathyroid synthesis of thyroid hormones is suggested. The importance of the unspecific histidine decarboxylase for the metabolism of histamine in mammals is discussed.