The effect of 5,5'-dithiobis(1-methyltetrazole) on cytoplasmic aldehyde dehydrogenase and its implications for cephalosporin-alcohol reactions.
Cephalosporin antibiotics with a 1-methyltetrazole-5-thio side chain have the ability to cause an unpleasant flushing reaction if they are taken some time before the drinking of alcohol. It is proposed that the explanation for this is that the side chain becomes liberated in vivo and oxidized to 5,5'-dithiobis(1-methyltetrazole) or to a mixed disulfide analogue which then inactivates aldehyde dehydrogenase. Support for this proposal is given by the results below concerning the interaction in vitro between the disulfides and sheep liver cytoplasmic aldehyde dehydrogenase. 5,5'-Dithiobis(1-methyltetrazole) has a rapid and pronounced inactivatory effect, very similar in many ways (though not identical) to that of disulfiram, to which it has a structural similarity. (Disulfiram is widely used therapeutically to deter alcoholics from drinking.) 1-Methyl-5-methylthiotetrazole (which is a simple model of the antibiotics) and the free 1-methyltetrazole-5-thiol have no effect on the enzyme in vitro, but methyl 5-(1-methyltetrazolyl) disulfide is a potent inactivator; this also supports the proposed pathway.
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D002511:Cephalosporins / Q000008:administration & dosage; D003593:Cytoplasm / Q000201:enzymology; D004220:Disulfides; D004221:Disulfiram / Q000494:pharmacology*; D004050:Ditiocarb; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D012756:Sheep; D013777:Tetrazoles / Q000494:pharmacology*
D001393:Azoles; D002511:Cephalosporins; D004220:Disulfides; D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; C001105:2,2'-dipyridyl disulfide; D000431:Ethanol; D015082:2,2'-Dipyridyl; C048500:5,5'-dithiobis(1-methyltetrazole); D004050:Ditiocarb; D000429:Alcohol Oxidoreductases; D005978:Glutathione; D004221:Disulfiram