TY - JOUR
T1 - Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue
T2 - Possible relationship to hypoprothrombinemia
AU - Wood, Thomas C.
AU - Johnson, Kenneth L.
AU - Naylor, Stephen
AU - Weinshilboum, Richard M.
PY - 2002/10
Y1 - 2002/10
N2 - Cephalosporin antibiotics with structures that include the heterocyclic leaving group 1-methyltetrazole-5-thiol (MTT) can cause hypoprothrombinemia and hemorrhage as a result of MTT-dependent inhibition of the γ-carboxylation of glutamate. The structure of cefazolin also includes a heterocyclic thiol, 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), and this compound can also inhibit the γ-carboxylation of glutamate. However, unlike MTT, which is known to be present in vivo after the administration of drugs that include this structure, there have been no reports that MTD is present in vivo after cefazolin administration. We set out to determine whether MTD might be present in the tissues of patients treated with cefazolin prior to surgery. To do that, we took advantage of the fact that heterocyclic thiols can undergo S-methylation catalyzed by the genetically polymorphic drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT). Initially, we tested recombinant human TPMT as a "reagent" to S-methylate MTD. MTD was a substrate for TPMT-catalyzed S-methylation, with an apparent Km value of 63 μM. Recombinant TPMT, with [14C-methyl]S-adenosyl-L-methionine as a cosubstrate, was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol preparations from patients who had been treated preoperatively with cefazolin. Pooled renal cytosol from 10 of those patients was used to purify and isolate the methylated product by reverse-phase high-performance liquid chromatography. That methylated compound coeluted with S-methyl MTD. When the methylated product was subjected to tandem mass spectrometry, it was identified as S-methyl MTD. Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway.
AB - Cephalosporin antibiotics with structures that include the heterocyclic leaving group 1-methyltetrazole-5-thiol (MTT) can cause hypoprothrombinemia and hemorrhage as a result of MTT-dependent inhibition of the γ-carboxylation of glutamate. The structure of cefazolin also includes a heterocyclic thiol, 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), and this compound can also inhibit the γ-carboxylation of glutamate. However, unlike MTT, which is known to be present in vivo after the administration of drugs that include this structure, there have been no reports that MTD is present in vivo after cefazolin administration. We set out to determine whether MTD might be present in the tissues of patients treated with cefazolin prior to surgery. To do that, we took advantage of the fact that heterocyclic thiols can undergo S-methylation catalyzed by the genetically polymorphic drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT). Initially, we tested recombinant human TPMT as a "reagent" to S-methylate MTD. MTD was a substrate for TPMT-catalyzed S-methylation, with an apparent Km value of 63 μM. Recombinant TPMT, with [14C-methyl]S-adenosyl-L-methionine as a cosubstrate, was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol preparations from patients who had been treated preoperatively with cefazolin. Pooled renal cytosol from 10 of those patients was used to purify and isolate the methylated product by reverse-phase high-performance liquid chromatography. That methylated compound coeluted with S-methyl MTD. When the methylated product was subjected to tandem mass spectrometry, it was identified as S-methyl MTD. Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway.
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U2 - 10.1124/dmd.30.10.1123
DO - 10.1124/dmd.30.10.1123
M3 - Article
C2 - 12228189
AN - SCOPUS:0036785430
SN - 0090-9556
VL - 30
SP - 1123
EP - 1128
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 10
ER -