title: N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia.
abstract: Several new antibiotics which contain an N-methyl-thio-tetrazole side chain have been associated with the development of hypoprothrombinaemia. This side chain was found to be capable of the in-vitro inhibition of a necessary reaction in the synthesis of prothrombin, the gamma carboxylation of glutamic acid. The 50% inhibitory concentration was 1.1 mmol/l. The intact antibiotics latamoxef, cephamandole, and cefoperazone, which contain the side chain, did not inhibit the reaction at concentrations up to 2 mmol/l. These results suggest that hypoprothrombinaemia associated with antibiotics containing N-methyl-thio-tetrazole side chains may be a consequence of the in-vivo degradation of these antibiotics and the subsequent inhibition of the gamma carboxylation of glutamic acid by the side chain.
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000378:metabolism; D001393:Azoles / Q000009:adverse effects*; D001419:Bacteria / Q000378:metabolism; D001711:Biotransformation; D002435:Cefamandole / Q000009:adverse effects; D002438:Cefoperazone; D002511:Cephalosporins / Q000009:adverse effects; D002513:Cephamycins / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006801:Humans; D007020:Hypoprothrombinemias / Q000139:chemically induced*; D007422:Intestines / Q000382:microbiology; D009070:Moxalactam; D011516:Prothrombin / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000009:adverse effects*
chemical_list: D000900:Anti-Bacterial Agents; D001393:Azoles; D002511:Cephalosporins; D002513:Cephamycins; D005971:Glutamates; D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; D018698:Glutamic Acid; D002435:Cefamandole; D002438:Cefoperazone; D011516:Prothrombin; D009070:Moxalactam