Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: effects of hemin and biliverdin.
Heme oxygenase-1 (HO-1), also known as heat shock protein 32, has been shown to protect against oxidant-induced tissue injury. In the present studies, we analyzed expression of this enzyme in macrophages and hepatocytes following acetaminophen administration and its potential role in hepatotoxicity. Treatment of rats with a hepatotoxic dose of acetaminophen (1 g/kg, ip) resulted in a time-dependent induction of HO-1 in the liver. This was observed within 6 h of acetaminophen administration in both hepatocytes and macrophages. Hepatocytes were found to be more sensitive than macrophages to the effects of acetaminophen on HO-1. Up regulation of HO-1 in the liver following acetaminophen administration correlated with induction of ferritin and manganese superoxide dismutase (MnSOD). To determine if HO-1 was hepatoprotective, rats were pretreated with hemin (30 micromol/kg, ip), a potent inducer of the enzyme. Following hemin treatment, we observed a time-dependent increase in HO-1 protein in the liver and in serum bilirubin levels. Pretreatment of rats with hemin was found to prevent acetaminophen-induced hepatotoxicity, as measured histologically and biochemically by decreased serum transaminase levels. This was correlated with more rapid increases in expression of hepatic ferritin and MnSOD. Heme metabolism via HO-1 generates biliverdin, which is rapidly converted to bilirubin by biliverdin reductase. Pretreatment of rats with biliverdin (40 micromol/kg, ip) was also found to block acetaminophen-induced injury. These data suggest that HO-1 is an important component of antioxidant defense during acetaminophen-induced hepatotoxicity.
Chiu
Hawjyh
H
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854-8020, USA.
Brittingham
Jennie A
JA
Laskin
Debra L
DL
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001664:Biliverdine / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D004790:Enzyme Induction; D005293:Ferritins / Q000096:biosynthesis; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D013047:Specific Pathogen-Free Organisms; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000637:Transaminases / Q000097:blood; D015854:Up-Regulation
D000082:Acetaminophen; D006427:Hemin; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D000637:Transaminases; D001664:Biliverdine