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Effect of N-methyl-thiotetrazole on vitamin K epoxide reductase
Abstract:
Clinical use of antibiotics containing a N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of a vitamin K-responsive hypoprothrombinemia. Administration of NMTT to rats decreased the activity of the liver microsomal vitamin K epoxide reductase, increased the liver ratio of vitamin K epoxide to vitamin K, and decreased the rate of metabolism of injected vitamin K epoxide. These responses are the same as those observed following the administration of coumarin anticoagulants. In contrast to the effect of coumarin anticoagulants, NMTT did not inhibit the vitamin K epoxide reductase in vitro. These data suggest that the hypoprothrombinemia which has been observed following use of these antibiotics results from the inactivation of the liver vitamin K epoxide reductase by NMTT or a NMTT metabolite.
Insights
Antibiotics with N-methyl-thiotetrazole (NMTT) side chains can cause vitamin K-responsive hypoprothrombinemia. NMTT inactivates liver vitamin K epoxide reductase, similar to coumarin anticoagulants, leading to bleeding risks.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Antibiotics containing N-methyl-thiotetrazole (NMTT) side chains are linked to vitamin K-responsive hypoprothrombinemia.
- Hypoprothrombinemia is a condition characterized by low levels of prothrombin, a protein crucial for blood clotting.
Purpose of the Study:
- To investigate the mechanism by which NMTT-containing antibiotics induce hypoprothrombinemia.
- To compare the effects of NMTT with known anticoagulant drugs, such as coumarin derivatives.
Main Methods:
- Administration of NMTT to rats.
- Measurement of liver microsomal vitamin K epoxide reductase activity.
- Analysis of the ratio of vitamin K epoxide to vitamin K in the liver.
- Assessment of the metabolism rate of injected vitamin K epoxide.
- In vitro testing of NMTT's effect on vitamin K epoxide reductase.
Main Results:
- NMTT administration decreased the activity of liver microsomal vitamin K epoxide reductase.
- The liver ratio of vitamin K epoxide to vitamin K increased after NMTT administration.
- The rate of metabolism of injected vitamin K epoxide decreased.
- NMTT did not inhibit vitamin K epoxide reductase in vitro, unlike coumarin anticoagulants.
Conclusions:
- The hypoprothrombinemia associated with NMTT-containing antibiotics likely results from the inactivation of liver vitamin K epoxide reductase by NMTT or its metabolites.
- NMTT exhibits a distinct mechanism of action compared to coumarin anticoagulants, despite producing similar physiological effects.