Inhibition of heme oxygenase-1 protects against tissue injury in carbon tetrachloride exposed livers.
OBJECTIVE
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.


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.
Eipel
Christian
C
Institute of Experimental Surgery, University of Rostock, Rostock, Germany.
Eisold
Michaela
M
Schuett
Harald
H
Vollmar
Brigitte
B
D000818:Animals; D001646:Bile / Q000378:metabolism; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism; D002251:Carbon Tetrachloride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008102:Liver Circulation / Q000187:drug effects; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D002248:Carbon Monoxide; D002251:Carbon Tetrachloride; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat