Role of metabolism in 1-bromopropane-induced hepatotoxicity in mice.
A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.
Lee
Sang Kyu
SK
College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
Kang
Mi Jeong
MJ
Jeon
Tae Won
TW
Ha
Hyun Woo
HW
Yoo
Jin Woo
JW
Ko
Gyu Sub
GS
Kang
Wonku
W
Jeong
Hye Gwang
HG
Lyoo
Won Seok
WS
Jeong
Tae Cheon
TC
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000187:drug effects / Q000378:metabolism; D006842:Hydrocarbons, Brominated / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D021241:Spectrometry, Mass, Electrospray Ionization; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006842:Hydrocarbons, Brominated; D017392:Thiobarbituric Acid Reactive Substances; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; C118559:1-bromopropane; D010634:Phenobarbital