BACKGROUND/AIMS:During the metabolism of the hepatotoxin carbon tetrachloride (CCl(4)) by cytochrome P450, heme, and free radicals are released. Heme oxygenase (HO-1) is an enzyme that is induced by heme as well as oxidative stress and has been reported to be involved in mediating protection against toxic liver injury. The purpose of the present study was to specify the role of HO-1 in CCl(4)-hepatotoxicity. METHODS AND RESULTS:We could demonstrate an up-regulation of HO-1 protein in CCl(4)-exposed liver tissue that reaches its maximum after 6 to 12 h, along with intrahepatic leukocyte accumulation and tissue injury. When animals were pretreated with hemin for augmentation of HO-1 expression, CCl(4)-exposure was associated with a reduction of intrahepatic leukocyte accumulation, while inhibition of CCl(4)-induced HO-1 expression by tin protoporphyrin-IX (SnPP-IX) enhanced leukocytic response. Of interest, however, liver morphology, transaminases, and bile flow as parameters of hepatocellular integrity and excretory function did not concur with reduced leukocyte numbers in the hepatic microcirculation, and revealed best organ function and tissue preservation in case of HO-1 inhibition by SnPP-IX. In contrast, hemin-treated CCl(4)-exposed livers demonstrated pathologic enzyme release and cholestasis. CONCLUSIONS:Taken together, inhibition of HO-1 in CCl(4)-hepatotoxicity protected the liver, while higher HO-1 activity harmed liver tissue, most probably due to interference of the HO-1 pathway with CCl(4)-dependent metabolism via cytochrome P450 and heme overload-associated toxicity.

The metabolism of the hepatotoxin CCl4 includes cytochrome P-450 and causes an elevation of free heme. Heme oxygenase (HO-1), an enzyme which is induced by heme and which catalyzes the oxidation of heme leads to the release of iron, vasodilative carbon monoxide and the antioxidant biliverdin. Thus, HO-1 could be of importance for the modulation and extent of hepatic injury upon acute CCl4- intoxication. In the present study, we could demonstrate an upregulation of HO-1 in CCl4-exposed liver tissue with a maximum at 12 h upon exposure together with a significant increase of venular leukocyte adherence, hepatocellular apoptosis and non-perfused sinusoids. In hemin-treated HO-1 overexpressing animals CCl4-exposure was associated with marked reduction of liver injury. Vice versa, inhibition of CCl4-induced HO-1 expression by SnPP-IX aggravated liver injury, implying a protective role of HO-1 in CCl4-induced liver injury.

The metabolism of the hepatotoxin CCl4 includes cytochrome P-450 and causes an elevation of free heme. Heme oxygenase (HO-1), an enzyme which is induced by heme and which catalyzes the oxidation of heme leads to the release of iron, vasodilative carbon monoxide and the antioxidant biliverdin. Thus, HO-1 could be of importance for the modulation and extent of hepatic injury upon acute CCl4intoxication. In the present study, we could demonstrate an upregulation of HO-1 in CCl4-exposed liver tissue with a maximum at 12 h upon exposure together with a significant increase of venular leukocyte adherence, hepatocellular apoptosis and non-perfused sinusoids. In hemin-treated HO-1 overexpressing animals CCl4-exposure was associated with marked reduction of liver injury. Vice versa, inhibition of CCl4-induced HO-1 expression by SnPP-IX aggravated liver injury, implying a protective role of HO-1 in CCl4-induced liver injury.