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 y-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 efilux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MIT or MUTT-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 MM dithiothreitol (DTI), but was inhibited by preincubation with GSSG at concentrations as low as 10 ;&M. 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 "y-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. (J. Clin. Invest. 1990Invest. . 86:1589Invest. -1594

Acetaminophen: A Liver Killer or Thriller

“…Alcohol exacerbates acetaminophen (paracetamol) hepatotoxicity by multiple mechanisms. Chronic alcohol consumption depletes hepatic glutathione, which helps neutralize NAPQI [2]. Chronic alcohol use can induce cytochrome P450 enzymes in the liver, specifically, CYP2E1, facilitating an increased conversion of acetaminophen to NAPQI [3].…”