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Ability of 1-methyltetrazole-5-thiol with microsomal activation to inhibit aldehyde dehydrogenase
1Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205.
Abstract:
Antibiotics that contain the 1-methyltetrazole-5-thiol (MTT) leaving group are associated with an adverse effect when alcohol is ingested after their administration. Therefore, the ability of MTT to inhibit an enzyme in alcohol metabolism, aldehyde dehydrogenase (ALDH), was examined. In the absence of microsomes, MTT did not inhibit ALDH obtained from either yeast or rat liver. In the presence of rat hepatic microsomes, MTT was able to inhibit the enzyme from both sources. The characteristics of the inhibition were studied, using the yeast enzyme, and found to be dependent upon the length of incubation with the hepatic microsomes and upon the concentration of MTT. Inhibition required the presence of NADH and was not detected if the microsomes were heat treated. Dilution did not reverse the inhibition. Intact antibiotics which contain the MTT moiety did not cause an inhibition of yeast ALDH unless the antibiotics were first treated with potassium hydroxide and then incubated with microsomes. Inhibition of ALDH activity measured in the mitochondrial plus microsomal fractions of rat liver also required NADH and was prevented by glutathione and heat treatment of the microsomes. These results indicate that microsomal activation of MTT is necessary for inhibition of aldehyde dehydrogenase. The behavior of MTT described here may explain the adverse effect observed if alcohol is ingested following administration of MTT-containing antibiotics.
Insights
The 1-methyltetrazole-5-thiol (MTT) group in some antibiotics can inhibit alcohol metabolism by blocking aldehyde dehydrogenase (ALDH). This inhibition requires activation by liver microsomes, explaining adverse effects when alcohol is consumed after taking these antibiotics.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Antibiotics containing the 1-methyltetrazole-5-thiol (MTT) moiety are linked to adverse reactions upon alcohol consumption.
- Aldehyde dehydrogenase (ALDH) is a critical enzyme in alcohol metabolism.
Purpose of the Study:
- To investigate the mechanism by which MTT affects ALDH activity.
- To determine if MTT is responsible for the observed adverse effects associated with MTT-containing antibiotics and alcohol.
Main Methods:
- Enzyme inhibition assays using purified yeast and rat liver ALDH.
- Incubation of MTT with rat hepatic microsomes and NADH.
- Analysis of ALDH activity following pre-incubation steps and varying concentrations of MTT and incubation times.
Main Results:
- MTT alone did not inhibit ALDH.
- MTT inhibited ALDH in the presence of rat hepatic microsomes and NADH, requiring prior incubation.
- Inhibition was dependent on incubation time, MTT concentration, and required intact microsomes (heat treatment abolished inhibition).
- Intact antibiotics containing MTT did not inhibit ALDH unless pre-treated.
Conclusions:
- Microsomal activation of MTT is essential for ALDH inhibition.
- The findings suggest that metabolically activated MTT is responsible for the adverse effects observed when alcohol is consumed after administration of MTT-containing antibiotics.