Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity.
Reductive metabolism of carbon tetrachloride (CCl(4)) is thought to cause lipid peroxidation which results in hepatic injury. Heme oxygenase-1 (HO-1) (EC 1.14.99.3), the rate-limiting enzyme in heme catabolism, is known to be induced by oxidative stress and to confer protection against oxidative tissue injuries. In this study, we examined the role of HO-1 induction in a rat model of CCl(4)-induced acute liver injury. CCl(4) treatment (1 mL/kg, intraperitoneally) produced severe hepatic injury in rats as revealed by significant increases in serum alanine transaminase (ALT) (EC 2.6.1.2) activity and hepatic malondialdehyde (MDA) content, severe liver cell injury, and increases in hepatic tumor necrosis factor-alpha (TNF-alpha) mRNA expression and DNA binding activity of nuclear factor-kappa B (NF-kappa B). Following CCl(4) treatment, hepatic HO-1 expression was markedly increased both at transcriptional and protein levels in hepatocytes, especially around the central vein. HO-1 induction was mediated in part through a rapid increase in microsomal free heme concentration presumably derived from hepatic cytochrome P450. Inhibition of HO activity by tin-mesoporphyrin (Sn-MP), which resulted in a sustained increase in microsomal free heme concentration, exacerbated liver injury, as judged by the sustained increase in serum ALT activity, extensive hepatocytes injuries, a more pronounced expression of hepatic TNF-alpha mRNA and an enhanced NF-kappa B activation. These findings indicate that induction of HO-1 is an adaptive response to CCl(4) treatment, and it may be critical in the recovery of hepatocytes from injury. Our findings also suggest that HO-1 induction may play an important role in conferring protection on hepatocytes from oxidative damage caused by free heme.
Nakahira
Kiichi
K
Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Takahashi
Toru
T
Shimizu
Hiroko
H
Maeshima
Kyoichiro
K
Uehara
Kenji
K
Fujii
Hiromi
H
Nakatsuka
Hideki
H
Yokoyama
Masataka
M
Akagi
Reiko
R
Morita
Kiyoshi
K
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D020011:Protective Agents / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000517:prevention & control
D020011:Protective Agents; D012333:RNA, Messenger; D006418:Heme; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital