Molecular toxicological analysis in abused-drug cocaine-induced liver injury-A study with knockout mice.

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Mechanism of cocaine-induced liver injury in mice has been analyzed. After pre-injection of phenobarbital for 5 days cocaine was administered to mice. Serum ALT values were measured at pre-phenobarbital injection (control), oh, 6h, 10h, 24h and 48h after cocaine injection. The ALT value showed peak top at 10h and/or 24h, and cocaine dose-dependent. The liver injury mainly observed marked necrosis of the cells in periportal region with infiltration of leukocytes. mRNA expression of iNOS in the liver enhanced at 10h and 24h than that of control or oh. N-acetylcysteine, carboxy PTIO and NG-monomethylarginine were post-injected 20-30 min after cocaine-administration. Serum ALT values at 10h were reduced to about 40%, 80% and 30% than those of saline injection, respectively. These results showed that cause of cocaine-induced liver injury was reactive-oxygen-species (ROS) including NO. iNOS was also suggested to relate with the oxidation mechanism. Next, the role of TNFα-TNFRI system was analyzed using TNFRI(-/-) (KO) mice in cocaine-induced liver injury. Serum ALT and AST values of KO mice were significantly higher than those of wild-type (WT) mice. H.-E., anti-MPO and anti-F4/80 staining of the liver in KO and WT mice showed the same tendency as the ALT values. From these results, it was suggested that TNFα-TNFRI system defensively acted in cocaine-induced liver injury of mouse.