Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with o...Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup;it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2- to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to desensitization of endotoxin responses since LPS was at least as effective when administered to DSS-pretreated rats. OS/RM gene repression may contribute to development of hepatotoxicity of carbamazepine in immune activation models.展开更多
文摘Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup;it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2- to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to desensitization of endotoxin responses since LPS was at least as effective when administered to DSS-pretreated rats. OS/RM gene repression may contribute to development of hepatotoxicity of carbamazepine in immune activation models.
文摘目的探讨氧化应激及炎性反应指标在缺血性脑卒中的临床意义。方法检测缺血性脑卒中(ischemic stroke,IS)患者和健康对照组血清中总抗氧化能力(total antioxidant capacity,TAC)、氧化型低密度脂蛋白(oxidized low density lipoprotein,Ox-LDL)、超氧化物歧化酶(super oxide dismutase,SOD)、超敏C反应蛋白(high sensitivity C reactive protein,Hs-CRP)等指标的表达,采用ELISA方法检测血清TAC、Ox-LDL;在贝克曼库尔特AU5821全自动生化分析仪上检测其他指标的水平。结果 (1)治疗组较正常对照组血清中TAC显著性降低,几乎为健康人水平的1/12(P<0.01),高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)、SOD的水平有所下降(P<0.05);(2)Hs-CRP、Ox-LDL、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)的水平显著性升高(均P<0.01),治疗组血清中Hs-CRP约为对照组的16倍,其OX-LDL水平约为1.7倍,LDL-C约为1.6倍。治疗组较对照组血清中氧化应激及炎性反应指标的表达差异有统计学意义。结论脑卒中的发生可能与氧化应激、炎性反应有重大关系。
