氯化汞对大鲵心脏和胰腺CYP2亚家族成员CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达的影响
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摘要
探究氯化汞(HgCl_2)对大鲵心脏和胰腺细胞色素P450 2(CYP2)亚家族成员细胞色素P450 2K1(CYP2K1)、P4502F3(CYP2F3)、P4502F5(CYP2F5)和P4502C19(CYP2C19)基因表达的影响,可为评价HgCl_2对大鲵的生态毒理影响提供基础数据.幼龄大鲵暴露于HgCl_2(1、10、100 ng/L)24、48、72 h后,采用qRT-PCR试验分析HgCl_2处理不同时间后CYP2亚家族成员CYP2K1、CYP2F3、CYP2F5和CYP2C19在心脏和胰腺中的表达变化模式.结果显示:HgCl_2对大鲵暴露24 h后,大鲵心脏CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达水平相对于对照组均呈现上升变化趋势,即1 ng/L HgCl_2显著诱导了大鲵心脏CYP2K1和CYP2C19基因表达水平(P <0.05),10 ng/L HgCl_2显著诱导了大鲵心脏CYP2F3和CYP2F5基因表达水平(P <0.05),100 ng/L HgCl_2均显著诱导了大鲵心脏CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达(P <0.05);大鲵胰腺CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达水平相对于对照组均呈现下降变化趋势,10、100 ng/L HgCl_2均显著抑制了大鲵胰腺CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达(P <0.05). HgCl_2对大鲵暴露48 h后,大鲵心脏CYP2F5基因表达水平相对于对照组均呈现显著下降变化趋势(P <0.05),并具有浓度梯度效应;大鲵胰腺CYP2F3基因表达水平受到显著诱导(P <0.05). HgCl_2对大鲵暴露72 h后,与对照相比大鲵心脏和胰腺CYP2K1、CYP2F3、CYP2F5和CYP2C19基因表达均无显著性变化.本研究表明随着HgCl_2暴露时间延长,CYP2亚家族基因表达无显著变化,大鲵心脏和胰腺CYP2亚家族基因CYP2K1、CYP2F3、CYP2F5和CYP2C19表达对HgCl_2刺激转变为慢性累积毒性效应;结果可为评价HgCl_2对大鲵的生态毒理影响提供基础数据.(图2表1参33)
The effects of mercuric chloride(HgCl_2) on the expression of the cytochrome P450 2 K1(CYP2 K1), cytochrome P4502 F3(CYP2 F3), cytochrome P450 2 F5(CYP2 F5), and cytochrome P450 2 C19(CYP2 C19) genes in the cytochrome P450 2(CYP2)subfamily in the heart and pancreas of the Chinese giant salamander, Andrias davidianus, were investigated in this study to provide basic data for evaluating the ecotoxicological effects of mercuric chloride on this species. Juvenile giant salamanders were continuously exposed to different concentrations of HgCl_2(0, 1, 10, and 100 ng/L) for 24, 48, and 72 h, and the effects of mercuric chloride on the expression of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in their heart and pancreas were investigated using real-time quantitative reverse transcriptase polymerase chain reaction(RT-qPCR). After exposure to HgCl_2 for 24 h, the expression levels of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in the hearts of giant salamanders were increased compared with those in the control group(exposed to 0 ng/L HgCl_2). In the hearts of giant salamanders exposed to 1 ng/L HgCl_2 for 24 h, the expression levels of the CYP2 K1 and CYP2 C19 genes were significantly increased(P < 0.05),while exposure to 10 ng/L HgCl_2 for 24 h significantly increased CYP2 F3 and CYP2 F5 gene expression levels(P < 0.05),and CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 gene expression levels were all significantly increased by exposure to 100 ng/L HgCl_2 for 24 h(P < 0.05). In the pancreases of giant salamanders, the expression levels of the CYP2 K1, CYP2 F3, CYP2 F5,and CYP2 C19 genes tended to be lower than those in the control group after exposure to HgCl_2 for 24 h. Exposure to both 10 and 100 ng/L HgCl_2 for 24 h significantly inhibited the expression of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in the pancreas(P < 0.05). After exposure to HgCl_2 for 48 h, the expression levels of CYP2 F5 in the hearts of giant salamanders significantly decreased in a dose-dependent manner(P < 0.05), and significantly elevated CYP2 F3 expression was found in the pancreas(P < 0.05). After exposure to HgCl_2 for 72 h, there were no significant changes in the expression levels of the CYP2 K1,CYP2 F3, CYP2 F5, and CYP2 C19 genes in the hearts and pancreases of giant salamanders compared with those in the control treatment(P > 0.05). It was concluded that no significant change in the expression of CYP2 subfamily genes occurred with increasing exposure time, which suggested that the responses of the CYP2 subfamily genes CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 in the heart and pancreas of the Chinese giant salamander may be converted into a chronic cumulative toxic effect in response to exposure to mercuric chloride exposure.
The effects of mercuric chloride(HgCl_2) on the expression of the cytochrome P450 2 K1(CYP2 K1), cytochrome P4502 F3(CYP2 F3), cytochrome P450 2 F5(CYP2 F5), and cytochrome P450 2 C19(CYP2 C19) genes in the cytochrome P450 2(CYP2)subfamily in the heart and pancreas of the Chinese giant salamander, Andrias davidianus, were investigated in this study to provide basic data for evaluating the ecotoxicological effects of mercuric chloride on this species. Juvenile giant salamanders were continuously exposed to different concentrations of HgCl_2(0, 1, 10, and 100 ng/L) for 24, 48, and 72 h, and the effects of mercuric chloride on the expression of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in their heart and pancreas were investigated using real-time quantitative reverse transcriptase polymerase chain reaction(RT-qPCR). After exposure to HgCl_2 for 24 h, the expression levels of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in the hearts of giant salamanders were increased compared with those in the control group(exposed to 0 ng/L HgCl_2). In the hearts of giant salamanders exposed to 1 ng/L HgCl_2 for 24 h, the expression levels of the CYP2 K1 and CYP2 C19 genes were significantly increased(P < 0.05),while exposure to 10 ng/L HgCl_2 for 24 h significantly increased CYP2 F3 and CYP2 F5 gene expression levels(P < 0.05),and CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 gene expression levels were all significantly increased by exposure to 100 ng/L HgCl_2 for 24 h(P < 0.05). In the pancreases of giant salamanders, the expression levels of the CYP2 K1, CYP2 F3, CYP2 F5,and CYP2 C19 genes tended to be lower than those in the control group after exposure to HgCl_2 for 24 h. Exposure to both 10 and 100 ng/L HgCl_2 for 24 h significantly inhibited the expression of the CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 genes in the pancreas(P < 0.05). After exposure to HgCl_2 for 48 h, the expression levels of CYP2 F5 in the hearts of giant salamanders significantly decreased in a dose-dependent manner(P < 0.05), and significantly elevated CYP2 F3 expression was found in the pancreas(P < 0.05). After exposure to HgCl_2 for 72 h, there were no significant changes in the expression levels of the CYP2 K1,CYP2 F3, CYP2 F5, and CYP2 C19 genes in the hearts and pancreases of giant salamanders compared with those in the control treatment(P > 0.05). It was concluded that no significant change in the expression of CYP2 subfamily genes occurred with increasing exposure time, which suggested that the responses of the CYP2 subfamily genes CYP2 K1, CYP2 F3, CYP2 F5, and CYP2 C19 in the heart and pancreas of the Chinese giant salamander may be converted into a chronic cumulative toxic effect in response to exposure to mercuric chloride exposure.
引文
1 Raghuvanshi R,Chaudhari A,Kumar GN.Amelioration of cadmiumand mercury-induced liver and kidney damage in rats by genetically engineered probiotic Escherichia coli Nissle 1917 producing pyrroloquinoline quinone with oral supplementation of citric acid[J].Nutrition,2016,32(11-12):1285-1294
2吴学祥,董然然,唐黎,聂福顺.贵州大鲵原生境的水质指标测定.贵州农业科学,2016,44(12):111-113[Wu XX,Dong RR,Tang L,Nie FS.Analysis on water quality from original habitat of giant salamander[J].Guizhou Agric Sci,2016,44(12):111-113]
3问思恩,李蝉,侯淑敏.陕西秦岭山区人工养殖大鲵肌肉中无机污染物含量分析[J].安徽农业科学,2011,39(16):9721-9722[Wen SE,Li C,Hou SM.Ananlysis of inorganic contaminants in giant salamander muscle of Qinling mountain in Shanxi[J].J Anh ui Agric Sci,2011,39(96):9721-9722]
4 Nelson DR,Marko PB,Baldwin WS.The cytochrome P450(CYP)gene superfamily in Daphnia pulex[J].BMC Genomics,2009,10(1):169
5 Zhang K,Wang X,Wu W,Wang Z,Huang S.Advances in conservation biology of Chinese giant salamander[J].Chin Biodiv,2002,10(3):291-297
6 Luo QH,Liu Y,Zhang LY.Effectiveness of releasing artificiallybred Chinese giant salamander(Andrias davidianus)into the wild in Zhangjiajie,Hunan[J].Biodiv Sci,2009,17(3):310-317
7 Kubota A,Bainy ACD,Woodin BR,Goldstone JV,Stegeman JJ.The cytochrome P450 2AA gene cluster in zebrafish(Danio rerio);expression of CYP2AA1 and CYP2AA2 and response to phenobarbital-type inducers[J].Toxicol Appl Pharmacol,2013,272(1):172-179
8 Haasch ML.Induction of anti-trout lauric acid hydroxylase immunoreactive proteins by peroxisome proliferators in bluegill and catfish[J].Mar En viron Res,1996,42(1):287-291
9 Zhu S,King SC,Haasch ML.Environmental induction of CYP1A-,CYP2M1-and CYP2K1-like proteins in tropical fish species by produced formation water on the northwest shelf of Australia[J].Mar Environ Res,2006,62(5-6):S322-S326
10 Kartha JS,Skordos KW,Sun H,Hall C,Easterwood LM,Reilly CA,Johnson EF,Yost GS.Single mutations change CYP2F3 from a dehydrogenase of 3-methylindole to an oxygenase[J].Biochemistry,2008,47(37):9756-9770
11 Li-Wan-Po A,Girard T,Farndon P,Cooley C,Lithgow J.Pharmacogenetics of CYP2C19:functional and clinical implications of a new variant CYP2C19*17[J].Br J Clin Pharmacol,2010,69(3):222-230
12 Hu Q,Meng Y,Wang D,Tian H,Xiao H.Characterization and function of the T-box 1 gene in Chinese giant salamander Andrias da vidianus[J]Genomics,2018,doi:10.1016/j.ygeno.2018.09.007
13 Wang C,Zhou YL,Zhu QH,Zhou ZK,Gu WB,Liu ZP,Wang LZ,Shu MA.Effects of heat stress on the liver of the Chinese giant salamander Andrias davidianus:histopathological changes and expression characterization of Nrf2-mediated antioxidant pathway genes[J].J Therm Biol,2018,76:115-125
14 Gao Y,Yang C,Gao H,Wang L,Yang C,Ji H,Dong W.Molecular characterisation of oestrogen receptor ERalpha and the effects ofbisphenol A on its expression during sexual development in the Chinese giant salamander(Andrias da vidianus)[J].Reprod Fertil Dev,2018,doi:10.1071/RD18107
15 Wang L,Yao J,Chen L,Chen J,Xue J,Jia W.Expression and possible functional roles of cytochromes P450 2J1(zfCyp 2J1)in zebrafish[J].Biochem Biophys Res Commun,2007,352(4):850-855
16 Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T))method[J].Methods,2001,25(4):402-408
17 Nakazawa El,Ikemoto T,Hokura A,Terada Y,Kunito T,Tanabe S,Nakai I.The presence of mercury selenide in various tissues of the striped dolphin:evidence fromμ-XRF-XRD and XAFS analyses[J].Metallomics,2011,3(7):719-725
18 Coelho JP,Santos H,Reis AT,Falcao J,Rodrigues ET,Pereira ME,Duarte AC,Pardal MA.Mercury bioaccumulation in the spotted dogfish(Scyliorhinus canicula)from the Atlantic Ocean[J].Mar Pollul Bull,2010,60(8):1372-1375
19 Fernandes AB,Barros FL,Pecanha FM,Wiggers GA,Frizera Vassallc P,Ronacher Simoes M,Fiorim J,Rossi de Batista P,Fioresi M,Rossoni L,Stefanon I,Alonso MJ,Salaices M,Valentim Vassallo D.Toxic effects of mercury on the cardiovascular and central nervous systems[J].J Biomed Biotechnol,2012,2012(3):949048
20 Houston MC.Role of mercury toxicity in hypertension,cardiovascular disease,and stroke[J].J Clin Hypertens(Greenwich),2011,13(8):621-627
21 Althurwi HN,Elshenawy OH,El-Kadi AO.Fenofibrate modulates cytochrome P450 and arachidonic acid metabolism in the heart and protects against isoproterenol-induced cardiac hypertrophy[J].J Cardiova sc Pharma col,2014,63(2):167-177
22 Elshenawy OH,Anwarmohamed A,Abdelhamid G,El-Kadi AO.Murine atrial HL-1 cell line is a reliable model to study drug metabolizing enzymes in the heart[J].Vascul Pharmacol,2013,58(4):326-333
23 Tse MY,Aboutabl ME,Althurwi HN,Elshenawy OH,Abdelhamid G,El-Kadi AO.Cytochrome P450 epoxygenase metabolite,14,15-EET,protects against isoproterenol-induced cellular hypertrophy in H9c2 rat cell line[J].Va scul Pharmacol,2013,58(5-6):363-373
24 Amara IE,Elshenawy OH,Abdelrady M,El-Kadi AO.Acute mercury toxicity modulates cytochrome P450,soluble epoxide hydrolase and their associated arachidonic acid metabolites in C57B1/6 mouse heart[J].Toxicol Lett,2014,226(1):53-62
25 Amara IE,Anwar-Mohamed A,Abdelhamid G,El-Kadi AO.Effect of mercury on aryl hydrocarbon receptor-regulated genes in the extrahepatic tissues of C57BL/6 mice[J].Food Chem Toxicol,2012,5C(7):2325-2334
26 Hu Q,Xiao H,Tian H,Meng Y.Identification and expression of cytochrome P450 genes in the Chinese giant salamander Andrias davidianus[J].Theriogenology,2017,95:62-68
27 Alexidis AN,Rekka EA,Kourounakis PN.Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies[J].Res Commun Mol Pathol Pharmacol,1994,85(1):67-72
28 Amara IE,Anwarmohamed A,Abdelhamid G,El-Kadi AO.Mercury modulates the cytochrome P450 1a1,1a2 and 1b1 in C57BL/6J mice:in vivo and in vitro studies[J].Toxicol Appl Pharmacol,2013,266(3):419-429
29 Joshi D,Mittal DK,Shukla S,Dixit VA.Curcuma longa,Linn,extract and curcumin protect CYP 2E1 enzymatic activity against mercuric chloride-induced hepatotoxicity and oxidative stress:a protective approach[J].Exp Toxicol Pathol,2017,69(6):373-382
30 Xiao GH,Song RK,Liu YG.Effects of some toxic metals on hepatic microsomal mixed function oxidase system of the rat[J].Acta Acad Med Wuhan,1984,4(3):158-162
31 Schumacher L,Abbott LC.Effects of methyl mercury exposure on pancreatic beta cell development and function[J].J Appl Toxicol,2016.37(1):4-12
32 Chen KL,Liu SH,Su CC,Yen CC,Yang CY,Lee KI,Tang FC,Chen YW,Lu TH,Su YC,Huang CF.Mercuric compounds induce pancreatic islets dysfunction and apoptosis in vivo[J].Int J Mol Sci,2012,13(10):12349-12366
33 Standop J,Schneider M,Ulrich A,Buchler MW,Pour PM.Differences in immunohistochemical expression of xenobiotic-metabolizing enzymes between normal pancreas,chronic pancreatitis and pancreatic cancer[J].Toxicol Pathol,2003,31(5):506-513
2吴学祥,董然然,唐黎,聂福顺.贵州大鲵原生境的水质指标测定.贵州农业科学,2016,44(12):111-113[Wu XX,Dong RR,Tang L,Nie FS.Analysis on water quality from original habitat of giant salamander[J].Guizhou Agric Sci,2016,44(12):111-113]
3问思恩,李蝉,侯淑敏.陕西秦岭山区人工养殖大鲵肌肉中无机污染物含量分析[J].安徽农业科学,2011,39(16):9721-9722[Wen SE,Li C,Hou SM.Ananlysis of inorganic contaminants in giant salamander muscle of Qinling mountain in Shanxi[J].J Anh ui Agric Sci,2011,39(96):9721-9722]
4 Nelson DR,Marko PB,Baldwin WS.The cytochrome P450(CYP)gene superfamily in Daphnia pulex[J].BMC Genomics,2009,10(1):169
5 Zhang K,Wang X,Wu W,Wang Z,Huang S.Advances in conservation biology of Chinese giant salamander[J].Chin Biodiv,2002,10(3):291-297
6 Luo QH,Liu Y,Zhang LY.Effectiveness of releasing artificiallybred Chinese giant salamander(Andrias davidianus)into the wild in Zhangjiajie,Hunan[J].Biodiv Sci,2009,17(3):310-317
7 Kubota A,Bainy ACD,Woodin BR,Goldstone JV,Stegeman JJ.The cytochrome P450 2AA gene cluster in zebrafish(Danio rerio);expression of CYP2AA1 and CYP2AA2 and response to phenobarbital-type inducers[J].Toxicol Appl Pharmacol,2013,272(1):172-179
8 Haasch ML.Induction of anti-trout lauric acid hydroxylase immunoreactive proteins by peroxisome proliferators in bluegill and catfish[J].Mar En viron Res,1996,42(1):287-291
9 Zhu S,King SC,Haasch ML.Environmental induction of CYP1A-,CYP2M1-and CYP2K1-like proteins in tropical fish species by produced formation water on the northwest shelf of Australia[J].Mar Environ Res,2006,62(5-6):S322-S326
10 Kartha JS,Skordos KW,Sun H,Hall C,Easterwood LM,Reilly CA,Johnson EF,Yost GS.Single mutations change CYP2F3 from a dehydrogenase of 3-methylindole to an oxygenase[J].Biochemistry,2008,47(37):9756-9770
11 Li-Wan-Po A,Girard T,Farndon P,Cooley C,Lithgow J.Pharmacogenetics of CYP2C19:functional and clinical implications of a new variant CYP2C19*17[J].Br J Clin Pharmacol,2010,69(3):222-230
12 Hu Q,Meng Y,Wang D,Tian H,Xiao H.Characterization and function of the T-box 1 gene in Chinese giant salamander Andrias da vidianus[J]Genomics,2018,doi:10.1016/j.ygeno.2018.09.007
13 Wang C,Zhou YL,Zhu QH,Zhou ZK,Gu WB,Liu ZP,Wang LZ,Shu MA.Effects of heat stress on the liver of the Chinese giant salamander Andrias davidianus:histopathological changes and expression characterization of Nrf2-mediated antioxidant pathway genes[J].J Therm Biol,2018,76:115-125
14 Gao Y,Yang C,Gao H,Wang L,Yang C,Ji H,Dong W.Molecular characterisation of oestrogen receptor ERalpha and the effects ofbisphenol A on its expression during sexual development in the Chinese giant salamander(Andrias da vidianus)[J].Reprod Fertil Dev,2018,doi:10.1071/RD18107
15 Wang L,Yao J,Chen L,Chen J,Xue J,Jia W.Expression and possible functional roles of cytochromes P450 2J1(zfCyp 2J1)in zebrafish[J].Biochem Biophys Res Commun,2007,352(4):850-855
16 Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T))method[J].Methods,2001,25(4):402-408
17 Nakazawa El,Ikemoto T,Hokura A,Terada Y,Kunito T,Tanabe S,Nakai I.The presence of mercury selenide in various tissues of the striped dolphin:evidence fromμ-XRF-XRD and XAFS analyses[J].Metallomics,2011,3(7):719-725
18 Coelho JP,Santos H,Reis AT,Falcao J,Rodrigues ET,Pereira ME,Duarte AC,Pardal MA.Mercury bioaccumulation in the spotted dogfish(Scyliorhinus canicula)from the Atlantic Ocean[J].Mar Pollul Bull,2010,60(8):1372-1375
19 Fernandes AB,Barros FL,Pecanha FM,Wiggers GA,Frizera Vassallc P,Ronacher Simoes M,Fiorim J,Rossi de Batista P,Fioresi M,Rossoni L,Stefanon I,Alonso MJ,Salaices M,Valentim Vassallo D.Toxic effects of mercury on the cardiovascular and central nervous systems[J].J Biomed Biotechnol,2012,2012(3):949048
20 Houston MC.Role of mercury toxicity in hypertension,cardiovascular disease,and stroke[J].J Clin Hypertens(Greenwich),2011,13(8):621-627
21 Althurwi HN,Elshenawy OH,El-Kadi AO.Fenofibrate modulates cytochrome P450 and arachidonic acid metabolism in the heart and protects against isoproterenol-induced cardiac hypertrophy[J].J Cardiova sc Pharma col,2014,63(2):167-177
22 Elshenawy OH,Anwarmohamed A,Abdelhamid G,El-Kadi AO.Murine atrial HL-1 cell line is a reliable model to study drug metabolizing enzymes in the heart[J].Vascul Pharmacol,2013,58(4):326-333
23 Tse MY,Aboutabl ME,Althurwi HN,Elshenawy OH,Abdelhamid G,El-Kadi AO.Cytochrome P450 epoxygenase metabolite,14,15-EET,protects against isoproterenol-induced cellular hypertrophy in H9c2 rat cell line[J].Va scul Pharmacol,2013,58(5-6):363-373
24 Amara IE,Elshenawy OH,Abdelrady M,El-Kadi AO.Acute mercury toxicity modulates cytochrome P450,soluble epoxide hydrolase and their associated arachidonic acid metabolites in C57B1/6 mouse heart[J].Toxicol Lett,2014,226(1):53-62
25 Amara IE,Anwar-Mohamed A,Abdelhamid G,El-Kadi AO.Effect of mercury on aryl hydrocarbon receptor-regulated genes in the extrahepatic tissues of C57BL/6 mice[J].Food Chem Toxicol,2012,5C(7):2325-2334
26 Hu Q,Xiao H,Tian H,Meng Y.Identification and expression of cytochrome P450 genes in the Chinese giant salamander Andrias davidianus[J].Theriogenology,2017,95:62-68
27 Alexidis AN,Rekka EA,Kourounakis PN.Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies[J].Res Commun Mol Pathol Pharmacol,1994,85(1):67-72
28 Amara IE,Anwarmohamed A,Abdelhamid G,El-Kadi AO.Mercury modulates the cytochrome P450 1a1,1a2 and 1b1 in C57BL/6J mice:in vivo and in vitro studies[J].Toxicol Appl Pharmacol,2013,266(3):419-429
29 Joshi D,Mittal DK,Shukla S,Dixit VA.Curcuma longa,Linn,extract and curcumin protect CYP 2E1 enzymatic activity against mercuric chloride-induced hepatotoxicity and oxidative stress:a protective approach[J].Exp Toxicol Pathol,2017,69(6):373-382
30 Xiao GH,Song RK,Liu YG.Effects of some toxic metals on hepatic microsomal mixed function oxidase system of the rat[J].Acta Acad Med Wuhan,1984,4(3):158-162
31 Schumacher L,Abbott LC.Effects of methyl mercury exposure on pancreatic beta cell development and function[J].J Appl Toxicol,2016.37(1):4-12
32 Chen KL,Liu SH,Su CC,Yen CC,Yang CY,Lee KI,Tang FC,Chen YW,Lu TH,Su YC,Huang CF.Mercuric compounds induce pancreatic islets dysfunction and apoptosis in vivo[J].Int J Mol Sci,2012,13(10):12349-12366
33 Standop J,Schneider M,Ulrich A,Buchler MW,Pour PM.Differences in immunohistochemical expression of xenobiotic-metabolizing enzymes between normal pancreas,chronic pancreatitis and pancreatic cancer[J].Toxicol Pathol,2003,31(5):506-513