Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction.
Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of mRNA for the nonspecific delta-aminolevulinate synthase. A transient but dramatic induction of HO-1 mRNA and a prolonged induction of heat shock protein 70 mRNA also occurred. The HO-1 protein was detected principally in the hepatocytes around the central vein. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activity and normal histology. Our findings in this study thus indicate that halothane-induced hepatotoxicity is due not only to its reductive metabolite formation, but also to an increase in hepatic free heme concentration, which is a potent prooxidant; HO-1 induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 prior to exposure to halothane, effectively prevents halothane-induced hepatotoxicity.
Odaka
Y
Y
Department of Anesthesiology and Resuscitology, Okayama University Medical School, Japan.
Takahashi
T
T
Yamasaki
A
A
Suzuki
T
T
Fujiwara
T
T
Yamada
T
T
Hirakawa
M
M
Fujita
H
H
Ohmori
E
E
Akagi
R
R
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006221:Halothane / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000187:drug effects; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010100:Oxygen / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
D018840:HSP70 Heat-Shock Proteins; D020011:Protective Agents; D012333:RNA, Messenger; D006418:Heme; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase; D000410:Alanine Transaminase; D010100:Oxygen; D006221:Halothane