Ability of 1-methyltetrazole-5-thiol with microsomal activation to inhibit aldehyde dehydrogenase.
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.
Lipsky
J J
JJ
Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205.
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology*; D001711:Biotransformation; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001393:Azoles; D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; D000444:Aldehyde Dehydrogenase; D005978:Glutathione