2,4-二羟基二苯甲酮对可卡因致小鼠肝毒性及神经毒性的保护作用  

Protective effect of 2,4-dihydroxybenzophenone on cocaine-induced hepatotoxicity and neurotoxicity in mice

作　　者：吴学银[1] 薛茹[1] 刘昕[1] 贾凤兰[1] 阮明[1] 张宝旭[1] 

机构地区：[1]北京大学公共卫生学院毒理学系,国家中医药管理局中药配伍减毒重点研究室,北京100191

出　　处：《北京大学学报（医学版）》2012年第3期421-425,共5页Journal of Peking University:Health Sciences

基　　金："重大新药创制"科技重大专项(2009ZX09103-007)资助~~

摘　　要：目的:探索2,4-二羟基二苯甲酮(2,4-dihydroxybenzophenone,BP-1)对可卡因所致肝毒性及神经毒性的保护作用,并对其作用机制进行初步探讨。方法:BP-1抗可卡因肝毒性实验采用雄性ICR小鼠,BP-1(100,200,400mg/kg体重)灌胃预给药4 d,末次给药30 min后,皮下注射给予可卡因75 mg/kg,24 h后处死。全自动生化仪检测血清中丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天冬氨酸氨基转移酶(aspartate aminotransferase,AST)和乳酸脱氢酶(lactate dehydrogenase,LDH)活性;制备肝匀浆,改良Hission法测定肝中还原型谷胱甘肽(reduced glu-tathione,GSH)、氧化型谷胱甘肽(oxidized glutathione,GSSG)含量,硫代巴比妥酸(thibabituric acid,TBA)法测定肝中丙二醛(malonaldehyde,MDA)含量;HE染色处理肝组织切片,光学显微镜观察病理学改变。BP-1抗可卡因神经毒性实验采用雄性ICR小鼠,BP-1(100,200,400 mg/kg体重)灌胃预给药3 d,末次给药30 min后,皮下注射给予可卡因20 mg/kg,记录小鼠0～180 min的自主活动次数。结果:BP-1抗可卡因致肝毒性实验结果发现,与溶剂对照组比较,可卡因模型组小鼠血清中ALT[(1 571±1 161)IU/L vs.(30±16)IU/L,P<0.05]、AST[(408±226)IU/L vs.(101±12)IU/L,P<0.05]和LDH[(3 963±1 431)IU/L vs.(1 935±287)IU/L,P<0.05]活性升高,差异有统计学意义。肝组织中GSH/GSSG比值[(5.11±0.63)vs.(6.88±1.13),P<0.05]下降,MDA含量[(1.97±1.36)μmol/g vs.(0.07±0.06)μmol/g,P<0.01]增加,差异有统计学意义。肝小叶中心出现大量坏死细胞。与可卡因模型组比较,BP-1各剂量组血清ALT[(112±96)IU/L,(54±20)IU/L,(35±15)IU/L,P<0.05]、AST[(130±33)IU/L,(107±5)IU/L,(99±9)IU/L,P<0.05]和LDH[(1 667±564)IU/L,(1 507±365)IU/L,(1 249±349)IU/L,P<0.01]水平显著降低,差异具有统计学意义。肝组织中GSH/GSSG比值[(7.33±1.84),(9.28±0.67),(10.5±1.20),P<0.05]升高,MDA[(1.82±1.19)μmol/g,(0.49±0.31)μmol/g,(0.35±0.30)μmol/g,P<0.05]含量下降,差异具有统计学意义。肝小叶中�Objective： To investigate the protective effect of 2,4-dihydroxybenzophenone （BP-1） on acute hepatotoxieity and neurotoxicity induced by cocaine in mice, and its possible mechanism. Me- thods：Male ICR mice were pretreated with BP-1 （I00,200,400 mg,/kg, ig, 4 d）, cocaine （75 mg/kg） was injected 30 minutes after BP-1 administration on day 4. Twenty-four hours after the injection of co- caine, the serum activities of alanine aminotransferase （ALT）, aspartate aminotransferase （AST） and lactate dehydrogenase （LDH） were assayed by HITACHI-7170A automatic analyzer. The content of ma- londialdehyde （MDA） and the content of reduced glutathione （GSH） and oxidized glutathione （GSSG） were examined, and the ratio of GSH/GSSG was calculated, and histopathological analyses were also made. Male ICR mice were pretreated with BP-1 （100,200,400 mg/kg, ig, 3 d）, cocaine（20 mg/kg） was injected 30 minutes after BP-1 administration on day 3. The locomotor activity during 0 - 180 minutes of mice was recorded individually for each animal immediately after cocaine injection. Results： After the administration of cocaine, compared with corresponding solvent group, the activities of ALT [ （1 571± 1 161）IU/L vs. （30 ±16） IU/L, P 〈0.05], AST [ （408 ±226） IU/L vs. （101 ± 12） IU/L, P 〈 0.05] and LDH [ （3 963 ± 1 431） IU/L vs. （1 935 ±287） IU/L, P 〈0.05] were significantly in- creased; the ratio of GSH/GSSG [ （5.11± 0.63 ） vs. （6.88 ± 1.13） ,P 〈 0.05 ] was decreased and the content of MDA [ （ 1.97 ±1.36）μmol/g vs. （0.07 ±0.06） μmol/g, P 〈0.01 ] was significantly increased. With the pretreatment of BP-1, compared with cocaine treatment group, the serum ALT [ （112 ±96 ）IU/L,（54±20） IU/L,（35 ±15） IU/L,P 〈0.05],AST [（130±33） IU/L,（107 ±5） IU/L, （99 ±9） IU/L, P 〈 0.05 ] and LDH [ （ 1 667 ± 564） IU/L, （ 1 507 ±365 ） IU/L, （ 1 249 ±349） IU/L, P 〈 0.01 ] were significantly decreased, the ratio

关 键 词：二苯甲酮类 可卡因 药物毒性 肝 神经系统 

分 类 号：R916.3[医药卫生—药学]