DEHP对大鼠肝组织及肝细胞色素P450酶系的影响
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摘要
为探讨邻苯二甲酸二(2-乙基己基)酯(DEHP)染毒对雄性大鼠肝组织及肝细胞色素P450(CYP450)酶系的影响,将32只SPF级SD雄性大鼠随机分为4组:(对照组,DEHP低,中,高剂量组),每组8只,分别以0,300,1000,3000mg/kg DEHP的剂量连续灌胃染毒28d.观察肝组织病理学变化;ELISA法测定肝脏CYP450、亚型CYP2E1和CYP3A1、以及孕烷X受体(PXR)水平.结果显示,HE染色可见低,中,高剂量DEHP暴露组肝脏组织分别出现炎性细胞浸润、充血、空泡和脂肪变性等不同程度的损伤;DEHP中,高剂量组大鼠CYP450酶含量分别为(203.61±34.44),(263.73±63.78)pmol/gprot,CYP2E1酶含量分别为(14.57±3.03),(20.06±2.90)U/gprot,均显著高于对照组(141.12±20.24)pmol/gprot,(10.76±2.24)U/gprot(P<0.01);低,中,高3个剂量组CYP3A1含量及PXR含量均同样显著高于对照组(P<0.05或P<0.01).DEHP暴露对大鼠肝组织有损伤作用,对肝脏CYP450、CYP2E1、CYP3A1以及上游调节因子PXR具有诱导效应.
To study the effects of di-(2-ethylhexyl) phthalate(DEHP) on hepatic tissue and cytochrome enzyme 450 in rat liver. A total of 32 male SD rats were randomly divided into 4groups(n=8per group): control group, low-dose group, medium-dose group, and high-dose group. DEHP was intragastrically administrated at the dosage of 0, 300, 1000 and 3000mg/kg(body weight) for 28 days. The pathological changes of hepatic tissues were observed by HE staining. ELISA method was used to determine the content of CYP450, CYP2E1, CYP3A1 and PXR. Inflammatory cellular infiltration, hyperemia, vacuoles and fatty degeneration were observed in the low, middle, and high dosage groups respectively. The contents of CYP450 and CYP2E1 in the middle dosage group [(203.61±34.44)pmol/gprot,(14.57±3.03)U/gprot] and in the high dosage group [(263.73±63.78)pmol/gprot,(20.06±2.90)U/gprot] were significantly higher than that of the control group [(141.12±20.24)pmol/gprot,(10.76±2.24)U/gprot](P<0.01). CYP3A1 and PXR in all dosage groups increased significantly compared with the control group(P<0.05, P<0.01). DEHP exposure induced the levels of CYP450, CYP2E1, CYP3A1 and PXR in rat liver.
To study the effects of di-(2-ethylhexyl) phthalate(DEHP) on hepatic tissue and cytochrome enzyme 450 in rat liver. A total of 32 male SD rats were randomly divided into 4groups(n=8per group): control group, low-dose group, medium-dose group, and high-dose group. DEHP was intragastrically administrated at the dosage of 0, 300, 1000 and 3000mg/kg(body weight) for 28 days. The pathological changes of hepatic tissues were observed by HE staining. ELISA method was used to determine the content of CYP450, CYP2E1, CYP3A1 and PXR. Inflammatory cellular infiltration, hyperemia, vacuoles and fatty degeneration were observed in the low, middle, and high dosage groups respectively. The contents of CYP450 and CYP2E1 in the middle dosage group [(203.61±34.44)pmol/gprot,(14.57±3.03)U/gprot] and in the high dosage group [(263.73±63.78)pmol/gprot,(20.06±2.90)U/gprot] were significantly higher than that of the control group [(141.12±20.24)pmol/gprot,(10.76±2.24)U/gprot](P<0.01). CYP3A1 and PXR in all dosage groups increased significantly compared with the control group(P<0.05, P<0.01). DEHP exposure induced the levels of CYP450, CYP2E1, CYP3A1 and PXR in rat liver.
引文
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[21]谢丹君,徐晶莹,诸葛淳淳,等.多环芳烃类物质对细胞色素P4501A1的诱导表达[J].同济大学学报(医学版),2013,34(2):1-5.
[22]马玉忠,刘玉芝,仲飞,等.安妥明对大鼠细胞色素酶P4503A1的影响[J].农业生物技术学报,2008,16(1):82-84.
[23]李苗,张育辉.DEHP对中国林蛙精巢中St AR、CYP17和CYP19基因表达的影响[J].生态学杂志,2012,31(7):1785-1790.
[24]田雨,李玲,李丰宝.邻苯二甲酸二丁酯和邻苯二甲酸二(2-乙基己基)酯联合染毒对雄性大鼠肝脏P450酶的影响[J].环境与健康杂志,2014,31(1):19-22.
[25]Kim N Y,Kim T H,Lee E,et al.Functional role of phospholipase D(PLD)in di(2-ethylhexyl)phthalate-induced hepatotoxicity in Sprague-Dawley rats.[J].Journal of Toxicology&Environmental Health,Part A.2010,73(21/22):1560-1569.
[26]胡冰芳,毕惠嫦,黄民.孕烷X受体及组成性雄甾烷受体的研究新进展[J].药学学报,2011,46(10):1173-1177.
[27]Kliewer S A.The nuclear pregnane X receptor regulates xenobiotic detoxification[J].Journal of Nutrition,2003,133(7):2444S-2447S.
[28]夏延哲,陈杰,潘裕华,等.6种中药单体对人孕烷X受体介导细胞色素酶P450 3A4转录的调节作用[J].热带医学杂志,2012,12(4):369-372.
[2]Svechnikova I,Svechnikov K,S?der O.The influence of di-(2-ethylhexyl)phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats[J].Journal of Endocrinology,2007,194(3):603-609.
[3]杨艳玲,徐晓虹.增塑剂DEHP的神经和行为发育毒性[J].心理科学进展,2013,21(6):1007-1013.
[4]王夫美,陈丽,焦姣,等.住宅室内降尘中邻苯二甲酸酯污染特征及暴露评价[J].中国环境科学,2012,32(5):780-786.
[5]耿梦娇,昌盛,刘琰,等.滹沱河冲洪积扇深层孔隙水中多环芳烃和酞酸酯的污染水平与饮水健康风险评估[J].中国环境科学,2016,36(12):3824-3830.
[6]Mckee R H,Butala J H,David R M,et al.NTP center for the evaluation of risks to human reproduction reports on phthalates:addressing the data gaps[J].Reproductive Toxicology,2004,18(1):1-22.
[7]Koch H M,Drexler H,Angerer J.An estimation of the daily intake of di(2-ethylhexyl)phthalate(DEHP)and other phthalates in the general population[J].International Journal of Hygiene and Environmental Health,2003,206(2):77-83.
[8]Guyton K Z,Chiu W A,Bateson T F,et al.A Reexamination of the PPAR-αActivation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants[J].Environmental Health Perspectives,2009,117(11):1664-1672.
[9]Swan S H.Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans[J].Environmental Research,2008,108(2):177-184.
[10]Koch H M,Preuss R,Angerer J D.Di(2-ethylhexyl)phthalate(DEHP):Human metabolism and internal exposure-an update and latest results1[J].International Journal of Andrology,2006,29(1):155-165.
[11]李晓宇,刘皋林.CYP450酶特性及其应用研究进展[J].中国临床药理学与治疗学,2008,13(8):942-946.
[12]Rocejanasaroj A,Tencomnao T,Sangkitikomol W.Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity,CYP450,and lipid metabolism gene expression in Hep G2cells[J].Genetics&Molecular Research,2014,13(1):205-219.
[13]生秀梅,熊丽,唐红枫,等.细胞色素P450酶系作为生物标志物在毒理学上的应用[J].四川环境,2005,24(3):74-78.
[14]Meskar A,Pleegautier E,Amet Y,et al.[Alcohol-xenobiotic interactions.Role of cytochrome P4502E1][J].Pathologie Biologie,2001,49(9):696-702.
[15]张荣,朱大岭.CYP3A基因表达分子机制的研究进展[J].医学研究杂志,2005,34(2):57-59.
[16]吴伟,瞿建宏,聂凤琴,等.多溴联苯醚胁迫下鲫鱼肝脏微粒体CYP3A1和GST的响应[J].生态环境学报,2009,18(3):805-810.
[17]孙坤.青蒿素类抗疟药与药物代谢酶相互作用研究[D].太原:山西医科大学,2011.
[18]张芳芳,朱心强.PXR、CAR和PPAR对UGT基因转录的调节[J].环境卫生学杂志,2005,32(2):99-104.
[19]周一平.用Excel软件进行药物毒理实验的随机分组[J].药学进展,2005,29(9):425-427.
[20]杨海峰,覃少华,江善祥.地塞米松和利福平对鸡肝CYP450酶系的影响[J].畜牧与兽医,2006,38(10):37-38.
[21]谢丹君,徐晶莹,诸葛淳淳,等.多环芳烃类物质对细胞色素P4501A1的诱导表达[J].同济大学学报(医学版),2013,34(2):1-5.
[22]马玉忠,刘玉芝,仲飞,等.安妥明对大鼠细胞色素酶P4503A1的影响[J].农业生物技术学报,2008,16(1):82-84.
[23]李苗,张育辉.DEHP对中国林蛙精巢中St AR、CYP17和CYP19基因表达的影响[J].生态学杂志,2012,31(7):1785-1790.
[24]田雨,李玲,李丰宝.邻苯二甲酸二丁酯和邻苯二甲酸二(2-乙基己基)酯联合染毒对雄性大鼠肝脏P450酶的影响[J].环境与健康杂志,2014,31(1):19-22.
[25]Kim N Y,Kim T H,Lee E,et al.Functional role of phospholipase D(PLD)in di(2-ethylhexyl)phthalate-induced hepatotoxicity in Sprague-Dawley rats.[J].Journal of Toxicology&Environmental Health,Part A.2010,73(21/22):1560-1569.
[26]胡冰芳,毕惠嫦,黄民.孕烷X受体及组成性雄甾烷受体的研究新进展[J].药学学报,2011,46(10):1173-1177.
[27]Kliewer S A.The nuclear pregnane X receptor regulates xenobiotic detoxification[J].Journal of Nutrition,2003,133(7):2444S-2447S.
[28]夏延哲,陈杰,潘裕华,等.6种中药单体对人孕烷X受体介导细胞色素酶P450 3A4转录的调节作用[J].热带医学杂志,2012,12(4):369-372.