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

This study aimed to examine whether acetaminophen (AAP), an anti-inflammato ry agent producing hepatocellular damages with its overdose, evokes hepatoc ellular dysfunction through mechanisms involving carbon monoxide (CO) gener ated by heme oxygenase (HO), In perfused rat livers, CO and bilirubin were determined in venous perfusate and bile samples as indices of heme degradat ion. Biliary excretion of transportally injected horseradish peroxidase was also determined to assess paracellular junctional permeability and vesicul ar transport across hepatocytes, AAP at 20 mmol/L induced a transient chole resis, followed by a reduction of bile output. Under these circumstances, t he release of CO and bilirubin IX alpha, terminal products of the HO-mediat ed 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 i ncrease in the junctional permeability that coincided with a reduction of v esicular transport across hepatocytes. Clotrimazole, a cytochrome P-450 inh ibitor, or zinc protoporphyrin IX, an HO inhibitor, but not copper protopor phyrin IX, which did not inhibit HO, attenuated these AAP-induced changes. Furthermore, administration of CO at concentrations comparable with those i nduced by AAP elicited a marked elevation of the paracellular junctional pe rmeability concurrent with a reduction of transcellular vesicular transport , mimicking effects of the AAP administration. Thus, CO serves as a putativ e regulator of hepatocellular function that is overproduced through acute h eme degradation during xenobiotic transformation.