Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species.
The modulating effects of nitric oxide (NO) and reactive oxygen species on cocaine-induced hepatotoxicity were examined by measuring plasma alanine aminotransferase activity and by carrying out histological studies. Liver injury was induced by a single injection of cocaine in adult male ICR mice. Pretreatment with aminoguanidine (an inhibitor of NO synthase), N-methyl-D-glucamine dithiocarbamate complex with iron ion (II) (Fe2+(MGD)2, a trapping reagent of NO) or deferoxamine complex with iron ion (III) (Fe3+-deferoxamine, a scavenger of NO) produced a marked inhibition of the hepatotoxicity induced by cocaine. In addition, pretreatment with allopurinol (an inhibitor of xanthine oxidase) and 1,3-dimethylthiourea (a scavenger of hydroxyl radical) also produced a potent inhibition. These findings suggest that a hydroxyl radical produced by the reaction of NO and superoxide anion (O2-) via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.
Aoki
K
K
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Ohmori
M
M
Takimoto
M
M
Ota
H
H
Yoshida
T
T
D000493:Allopurinol / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000502:physiology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006146:Guanidines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000493:Allopurinol; D019001:Nitric Oxide Synthase; D003042:Cocaine; C004479:pimagedine