Carbon monoxide-mediated alterations in paracellular permeability and vesicular transport in acetaminophen-treated perfused rat liver

Mikiji Mori, Makoto Suematsu, Takanori Kyokane, Tsuyoshi Sano, Hidekazu Suzuki, Tokio Yamaguchi, Yuzuru Ishimura, Hlromasa Ishii

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31 Citations (Scopus)

Abstract

This study aimed to examine whether acetaminophen (AAP), an anti- inflammatory agent producing hepatocellular damages with its overdose, evokes hepatocellular dysfunction through mechanisms involving carbon monoxide (CO) generated by heme oxygenase (HO). In perfused rat livers, CO and bilirubin were determined in venous perfusate and bile samples as indices of heme degradation. Biliary excretion of transportally injected horseradish peroxidase was also determined to assess paracellular junctional permeability and vesicular transport across hepatocytes. AAP at 20 mmol/L induced a transient choleresis, followed by a reduction of bile output. Under these circumstances, the release of CO and bilirubin IXα, terminal products of the HO-mediated heme degradation, became 2.5-fold greater than the control. The rate of CO production appeared stoichiometric to the degradation rate of microsomal cytochrome P-450. Mechanisms for the AAP-induced cholestasis involved an increase in the junctional permeability that coincided with a reduction of vesicular transport across hepatocytes. Clotrimazole, a cytochrome P-450 inhibitor, or zinc protoporphyrin IX, an HO inhibitor, but not copper protoporphyrin IX, which did not inhibit HO, attenuated these AAP- induced changes. Furthermore, administration of CO at concentrations comparable with those induced by AAP elicited a marked elevation of the paracellular junctional permeability concurrent with a reduction of transcellular vesicular transport, mimicking effects of the AAP administration. Thus, CO serves as a putative regulator of hepatocellular function that is overproduced through acute heme degradation during xenobiotic transformation.

Original languageEnglish
Pages (from-to)160-168
Number of pages9
JournalHepatology
Volume30
Issue number1
DOIs
Publication statusPublished - 1999 Jul 8

ASJC Scopus subject areas

  • Hepatology

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