Mechanism of the inhibition of the gamma-carboxylation of glutamic acid by N-methylthiotetrazole-containing antibiotics.

Abstract

Antibiotics that contain a 1-N-methyl-5-thiotetrazole (MTT) side group were associated with hypoprothrombinemia. In a detergent-treated rat liver microsomal system, MTT inhibited the carboxylation of the .gamma. carbon of glutamic acid, a necessary reaction in the synthesis of 4 of the clotting factors. The inhibition by MTT was slow in onset, with a lag time of 15 min before significant inhibition occurred. A preincubation of MTT with the microsomes decreased the lag time and increased the extent of inhibition. Glutathione 1 mM markedly decreased the ability of MTT to inhibit this reaction. The disulfide dimer of MTT was a more potent inhibitor of the system than was MTT, with inhibition detected as low as 1 .mu.M dimer. Disulfiram also inhibited the carboxylation system. Evidently, the SH group of MTT is important for the inhibitory effect of MTT. A slowly formed metabolite of MTT may be directly responsible for the observed inhibition. The inhibitory mechanism of MTT may be analogous to that of disulfiram, which would explain some pharmacologic effects in common with disulfiram. These in vitro observations and a closer examination of the clinical evidence raise the possibility that MTT-containing antibiotic-induced hypoprothrombinemia may not be a vitamin K reversible phenomenon.