Cephalosporin-induced alteration in hepatic glutathione redox state

A potential mechanism for inhibition of hepatic reduction of vitamin K1;2,3-epoxide in the rat

Mack C. Mitchell, Ariane Mallat, James J. Lipsky

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6 Citations (Scopus)

Abstract

Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal γ-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism. Dose-related increases in biliary efflux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MTT or MTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 μM dithiothreitol (DTT), but was inhibited by preincubation with GSSG at concentrations as low as 10 μM. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal γ-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics.

Original languageEnglish (US)
Pages (from-to)1589-1594
Number of pages6
JournalJournal of Clinical Investigation
Volume86
Issue number5
StatePublished - Nov 1990

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Cephalosporins
Glutathione Disulfide
Sulfhydryl Compounds
Oxidation-Reduction
Glutathione
Liver
Hypoprothrombinemias
Dithiothreitol
Vitamin K 1
Anti-Bacterial Agents
Vitamin K
vitamin K1 oxide
Disulfides
Intravenous Administration

Keywords

  • γ-carboxylation
  • Drug metabolism
  • Methyltetrazole thiol
  • Prothrombin time
  • Thiocarbamides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Cephalosporin-induced alteration in hepatic glutathione redox state: A potential mechanism for inhibition of hepatic reduction of vitamin K1;2,3-epoxide in the rat",
abstract = "Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal γ-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism. Dose-related increases in biliary efflux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MTT or MTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 μM dithiothreitol (DTT), but was inhibited by preincubation with GSSG at concentrations as low as 10 μM. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal γ-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics.",
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T1 - Cephalosporin-induced alteration in hepatic glutathione redox state

T2 - A potential mechanism for inhibition of hepatic reduction of vitamin K1;2,3-epoxide in the rat

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AU - Mallat, Ariane

AU - Lipsky, James J.

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N2 - Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal γ-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism. Dose-related increases in biliary efflux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MTT or MTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 μM dithiothreitol (DTT), but was inhibited by preincubation with GSSG at concentrations as low as 10 μM. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal γ-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics.

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