Antibiotics that contain a
1-N-methyl-5-thiotetrazole (MTT) side group have been 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 four of the
clotting factors. In the present work, the inhibition by MTT was found to be 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 at 1 mM was found to markedly decrease 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 microM dimer.
Disulfiram also inhibited the carboxylation system. These results indicate that the sulfhydryl group of MTT is important for the inhibitory effect of MTT and suggest that 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. In addition, the in vitro observations presented here 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.