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

分析了可卡因致小鼠肝损伤的机制。小鼠经苯巴比妥预注射5天后给予可卡因。测定注射苯巴比妥前（对照）、注射可卡因后oh、6h、10h、24h、48h血清ALT值。ALT值在10h和/或24h出现峰值，且呈剂量依赖性。肝损伤主要表现为门静脉周围区细胞明显坏死，白细胞浸润。肝脏iNOS mRNA表达在10h和24h较对照组和oh增强。给药后20 ~ 30 min注射n -乙酰半胱氨酸、羧基PTIO和ng -单甲基精氨酸。10h时血清ALT值分别较生理盐水注射降低约40%、80%和30%。结果表明，可卡因所致肝损伤的主要原因是NO等活性氧（ROS）。iNOS也被认为与氧化机制有关。接下来，利用TNFRI(-/-) （KO）小鼠分析tnf - α-TNFRI系统在可卡因性肝损伤中的作用。KO小鼠血清ALT和AST值显著高于野生型（WT）小鼠。纳米比亚。KO和WT小鼠肝脏抗mpo和抗f4 /80染色与ALT值呈相同趋势。提示tnf - α- tnfri系统在可卡因致小鼠肝损伤中具有防御作用。

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.