Oka T, Touchi A, Ezumi K, Yamakawa M, Matsubara T
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Jpn J Pharmacol. 1988 Feb;46(2):165-72. doi: 10.1254/jjp.46.165.
The in vitro effect of N-methyltetrazolethiol (NMTT), one of the common substituents at the 3'-position of the cephem in various beta-lactam antibiotics, on liver microsomal gamma-glutamylcarboxylation (gamma-carboxylation) activity was examined using solubilized rat liver enzyme. The enzyme activity was inhibited by coexisting with NMTT and NADH, and this inhibitory activity could be suppressed by the addition of a sulfhydryl compound such as dithiothreitol (DTT), glutathione or cysteine. Various five-membered heterocyclic thiol compounds exhibited concentration-dependent inhibition of microsomal gamma-carboxylation activity. These inhibitory actions diminished markedly in the presence of 1 mM DTT. In vitro gamma-carboxylation activity also decreases upon addition of various beta-lactam antibiotics at 1 or 10 mM, depending upon the concentration of the drug. Among the heterocyclic thiol compounds, there is a correlation between their inhibitory activities and hydrophobicities. Thus, the in vitro inhibitory activity of heterocyclic thiol compounds and beta-lactam antibiotics on microsomal gamma-carboxylation activity is not correlated with their molecular structures, but rather depends on their hydrophobicities and with the concentrations in the reaction mixture.
N-甲基四唑硫醇（NMTT）是各种β-内酰胺抗生素中头孢烯3'-位常见的取代基之一，使用溶解的大鼠肝脏酶检测了其对肝脏微粒体γ-谷氨酰羧化（γ-羧化）活性的体外作用。该酶活性在与NMTT和NADH共存时受到抑制，并且这种抑制活性可以通过添加二硫苏糖醇（DTT）、谷胱甘肽或半胱氨酸等巯基化合物来抑制。各种五元杂环硫醇化合物对微粒体γ-羧化活性表现出浓度依赖性抑制。在1 mM DTT存在下，这些抑制作用明显减弱。添加1或10 mM的各种β-内酰胺抗生素后，体外γ-羧化活性也会降低，这取决于药物的浓度。在杂环硫醇化合物中，它们的抑制活性与疏水性之间存在相关性。因此，杂环硫醇化合物和β-内酰胺抗生素对微粒体γ-羧化活性的体外抑制活性与其分子结构无关，而是取决于它们的疏水性以及反应混合物中的浓度。
