Suttie J W, Engelke J A, McTigue J
Biochem Pharmacol. 1986 Jul 15;35(14):2429-33. doi: 10.1016/0006-2952(86)90472-7.
The use of a number of antibiotics which contain an N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of hypoprothrombinemia. The suggested role of NMTT as an inhibitor of the liver microsomal vitamin K-dependent carboxylase has been investigated. In standard incubations, NMTT had no effect on carboxylation when vitamin KH2 was a substrate but was a weak inhibitor when [vitamin K + NADH] was a substrate. Microsomal vitamin K reductases, however, were not inhibited by NMTT. Preincubation of the incubation mixture with NADH and NMTT resulted in inhibition of carboxylase activity when either vitamin KH2 or [vitamin K + NADH] was the substrate. A fraction of the microsomal membrane which was not readily solubilized by dilute detergent protected the enzyme from this inhibition. The data suggest that NMTT is metabolized to an active inhibitor or is able to covalently inactivate the enzyme in the presence of NMTT. The vitamin K responsiveness of the clinically observed hypoprothrombinemia suggests that it is not related to this in vitro inhibition of the vitamin K-dependent carboxylase.
据报道，使用多种含有N-甲基-硫代四氮唑（NMTT）侧链的抗生素会导致低凝血酶原血症的发病率增加。人们对NMTT作为肝脏微粒体维生素K依赖性羧化酶抑制剂的潜在作用进行了研究。在标准孵育实验中，当维生素KH2作为底物时，NMTT对羧化作用没有影响，但当[维生素K + NADH]作为底物时，NMTT是一种弱抑制剂。然而，微粒体维生素K还原酶不受NMTT抑制。当维生素KH2或[维生素K + NADH]作为底物时，将孵育混合物与NADH和NMTT预孵育会导致羧化酶活性受到抑制。微粒体膜中不易被稀洗涤剂溶解的一部分可保护该酶免受这种抑制。数据表明，NMTT被代谢为活性抑制剂，或者能够在NMTT存在的情况下使该酶共价失活。临床观察到的低凝血酶原血症对维生素K的反应表明，它与体外对维生素K依赖性羧化酶的这种抑制无关。
