附子双酯型二萜生物碱对代谢酶的影响及心肌毒性研究进展
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摘要
附子是一种常用的中草药,具有广泛的药理作用,但心脏毒性显著。其主要毒性成分为双酯型二萜生物碱,如:乌头碱、中乌头碱、次乌头碱,如何减轻附子毒性但又不影响药效格外重要。多年来,众多学者不断深入研究附子生物碱的毒性机制,并取得了一定的共识。文章通过总结国内外研究资料,阐述了附子所含有的双酯型二萜生物碱对细胞色素P450酶系的影响,以及与其心脏毒性相关心肌的氧化损伤、细胞凋亡、缝隙连接蛋白Cx43和钠、钾、钙离子稳态的影响,并阐述了与上述机制相关的甘草、人参与附子配伍的作用机制。
Fuzi is a commonly used Chinese herbal medicine with a wide range of pharmacological effects, but the cardiotoxicity was significant. Its main toxic components are diester diterpenoid alkaloids, such as aconitine,hypaconitine and mesaconitine. How to reduce Fuzi toxicity without affecting drug efficacy is particularly important.Over the years, many scholars have been studying in depth the toxicity mechanism of alkaloids in Fuzi and achieved a certain degree of consensus. By summarizing domestic and foreign research data, this article describes the effects of diester-diterpenoid alkaloids contained in Fuzi on cytochrome P450 enzymes, as well as the oxidative damage,apoptosis, gap junction protein Cx43, and Na~+, K~+, Ca~(2+) homeostasis of the myocardium associated with its cardiotoxicity. The mechanism of compatibility of Fuzi-Gancao, Fuzi-Renshen associated with the above mechanisms are described.
Fuzi is a commonly used Chinese herbal medicine with a wide range of pharmacological effects, but the cardiotoxicity was significant. Its main toxic components are diester diterpenoid alkaloids, such as aconitine,hypaconitine and mesaconitine. How to reduce Fuzi toxicity without affecting drug efficacy is particularly important.Over the years, many scholars have been studying in depth the toxicity mechanism of alkaloids in Fuzi and achieved a certain degree of consensus. By summarizing domestic and foreign research data, this article describes the effects of diester-diterpenoid alkaloids contained in Fuzi on cytochrome P450 enzymes, as well as the oxidative damage,apoptosis, gap junction protein Cx43, and Na~+, K~+, Ca~(2+) homeostasis of the myocardium associated with its cardiotoxicity. The mechanism of compatibility of Fuzi-Gancao, Fuzi-Renshen associated with the above mechanisms are described.
引文
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[2]Ameri A.The effects of aconitum alkaloids on the central nervous system[J].Progress in Neurobiology,1998,56(2):211-235.
[3]Omura T.Forty years of cytochrome P450[J].Biochemical and Biophysical Research Communications,1999,266(3):690-698.
[4]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.
[5]Axel M,Dagmar S,Peter HR,et al.Expression and inducibility of cytochrome P450 3A9(CYP3A9)and other members of the CYP3A subfamily in rat liver[J].Archives of Biochemistry and Biophysics,1997,337(1):1-7.
[6]Kiyoshi N,Makoto O,Miki S,et al.Structure and expression of the rat CYP3A1 gene:isolation of the gene(P450/6βB)and characterization of the recombinant protein[J].Archives of Biochemistry and Biophysics,1999,362(2):242-253.
[7]Lan T,Ling Y,Chang L,et al.Involvement of CYP3A4/5and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes[J].Toxicology Letters,2011,202(1):47-54.
[8]Ling Y,Tao W,Yang CH,et al.Microsomal cytochrome P450-mediated metabolism of hypaconitine,an active and highly toxic constituent derived from Aconitum species[J].Toxicology Letters,2011,204(1):81-91.
[9]Ling Y,Lan T,Yun G,et al.Characterization of metabolites and human P450 isoforms involved in the microsomal metabolism of mesaconitine[J].Xenobiotica,2011,41(1):46-58.
[10]Wang YG,Wang SQ,Liu YX,et al.Characterization of metabolites and cytochrome P450 isoforms involved in the microsomal metabolism of aconitine[J].Journal of Chromatography B,2006,844(2):292-300.
[11]毕云枫,刘舒,张瑞兴,等.UPLC-MS/MS方法研究中乌头碱的大鼠CYP450代谢产物及途径[J].药学学报,2013,48(12):1823-1828.
[12]毕云枫,李雪,皮子凤,等.UPLC-MS/MS方法研究次乌头碱在大鼠肝微粒体CYP450中的体外代谢产物及代谢酶亚型[J].质谱学报,2013,34(6):330-337.
[13]李晗,王宇光,马增春,等.乌头碱、新乌头碱和次乌头碱对CYP3A4抑制作用研究[J].中国新药杂志,2017,26(9):999-1004.
[14]Shou MG,Lu T,Kristopher WK,et al.Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism[J].European Journal of Pharmacology,2000,394(2):199-209.
[15]Zhu LJ,Yang XS,Zhou J,et al.The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultraperformance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone[J].Food and Chemical Toxicology,2013,51:396-403.
[16]Wu JJ,Cheng ZX,Zhu LJ,et al.Coadministration of Pinellia ternata Can signifcantly reduce aconitum carmi-chaelii to inhibit CYP3A Activity in Rats[J].Evidence-Based Complementary and Alternative Medicine,2014:1-10.
[17]Xiao Y,Ma ZC,Wang YG,et al.Cardioprotection of Shenfu preparata on cardiac myocytes through cytochrome P450[J].Journal of Integrative Medicine,2013,11(5):327-336.
[18]Skrupskii Va,Plaksin SE.Changes in the fatty acid composition of the phospholipids in the internal organs of rats during the modelling of aconitine arrhythmia[J].Eksp Klin Farmakol,1994,57(4):53-55.
[19]张琦,张大方.乌头类生物碱对慢性心衰大鼠心肌SOD活性和MDA含量的影响[J].时珍国医国药,2010,21(11):2812-2813.
[20]Gao XT,Zhang XC,Hu J,et al.Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria mediated pathway[J].Molecular Medicine Reports,2018,17(1):284-292.
[21]Ding F,Shao ZW,Yang SH,et al.Role of mitochondrial pathway in compression-induced apoptosis of nucleus pulposus cells[J].Apoptosis,2012,17:579-590.
[22]梁先敏.Caspase和JNK/SAPK、p38 MAPK与细胞凋亡[J].国外医学卫生学分册,2008,35(1):5-10.
[23]Sun GB,Sun H,Meng XB,et al.Aconitine-induced Ca2+overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats[J].Toxicology and Applied Pharmacology,2014,279(1):8-22.
[24]Alexander Db,Goldberg-GS.Transfer of biologically important molecules between cells through gap junction channals[J].Curr Med Chem,2003,10(19):2045-2058.
[25]Goran S,Klaus W.Gap junctions and the connexin protein family[J].Cardiovascular Research,2004,62(2):228-232.
[26]Stephan BD,Liu FY,Zhang J,et al.Modulation of cardiac gap junction expression and arrhythmic susceptibility[J].Circ Res,2004,95(10):1035-1041.
[27]Zhang SW,Liu Y,Huang GZ,et al.Aconitine alters connexin43 phosphorylation status and[Ca2+]oscillation patterns in cultured ventricular myocytes of neonatal rats[J].Toxicology in Vitro,2007,21(8):1476-1485.
[28]李志勇,谭鹏,孙建宁,等.次乌头碱对乳大鼠原代培养心肌细胞Ca2+及Cx43表达的影响[J].时珍国医国药,2011,22(11):2689-2691.
[29]Rao S,Sikdar-SK.Modification of alpha subunit of RIIA sodium channels by aconitine[J].Pflugers Arch,2000,439(3):349-355.
[30]Wright SN.Comparison of aconitine-modified human heart(h H1)and rat skeletal(1)muscle Na+channels:an important role for external Na+ions[J].Journal of Physiology,2002,538(3):759-771.
[31]Wang SY,Wang GK.Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins[J].Cellular Signalling,2003,15(2):151-159.
[32]龚冬梅,单宏丽,周宇宏,等.哇巴因和乌头碱诱发豚鼠和大鼠心律失常的离子作用靶点[J].药学学报,2004,39(5):328-332.
[33]董晞,赵世萍,刘岩,等.甘草苷对乌头碱致心肌细胞损伤的保护作用[J].中华中医药杂志,2009,24(2):163-166.
[34]Wang YJ,Chen BS,Lin MW,et al.Time-dependent block of ultrarapid-delayed rectier K1 currents by aconitine,a potent cardiotoxin,in heart-derived H9c2 myoblasts and in neonatal rat ventricular myocytes[J].Toxicological Sciences,2008,106(2):454-463.
[35]Ole HP,Michalak M,Verkhratsky A.Calcium signalling:Past,present and future[J].Cell Calcium,2005,38(3):161-169.
[36]李志勇,谭鹏,赵晖,等.次乌头碱对心肌细胞Ca2+调控蛋白m RNA表达的影响[J].重庆医学,2011,40(25):2546-2548.
[37]Geoffrey SP,Roger DZ,Andy H,et al.Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of Ltype Ca2+channels[J].The Journal of Biological Chemistry,2001,276(33):30794-30802.
[38]Fabien B,Jerome L,Le Guennec J,et al.Ca2+currents in cardiac myocytes:Old story,new insights[J].Progress in Biophysics and Molecular Biology,2006,91:1-82.
[39]Zhou YH,Piao XM,Liu X,et al.Arrhythmogenesis toxicity of aconitine is related to intracellular Ca2+signals[J].International Journal of Medical Sciences,2013,10(9):1242-1249.
[40]Wu JJ,Wang XC,Chung YY,et al.L-Type calcium channel inhibition contributes to the proarrhythmic effects of aconitine in human cardiomyocytes[J].Plos one,2017,12(1):1-18.
[41]Fu M,Wu M,Wang JF,et al.Disruption of the intracellular Ca2+homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes[J].Biochemical and Biophysical Research Communications,2007,354(4):929-936.
[42]沈少华,张宇燕,杨洁红,等.附子甘草配伍与炮制对乌头碱含量影响的比较研究[J].中华中医药学刊,2009,27(2):367-369.
[43]Wu JJ,Cheng ZX,Chen H,et al.The significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction The necessity of combination therapy of radix Aconiti[J].Journal of Ethnopharmacology,2015,170(1):251-254.
[44]周天梅,杨洁红,万海同,等.附子甘草主要成分配伍对乌头碱致大鼠传代心肌细胞损伤的保护作用[J].北京中医药大学学报,2014,37(1):22-27.
[45]刘巧云,张宇燕,万海同,等.甘草苷、甘草次酸与次乌头碱配伍的研究[J].中华中医药学刊,2013,31(3):493-495.
[46]Zhang YY,Yu L,Jin WF,et al.Reducing toxicity and increasing efficiency aconitine with liquiritin and glycyrrhetinic acid regulate calcium regulatory proteins in rat myocardial cell[J].Afr J Tradit Complement Altern Med,2017,14(4):69-79.
[47]董晞,赵世萍,刘岩,等.甘草苷对乌头碱致心肌细胞损伤的保护作用[J].中华中医药杂志,2009,24(2):163-166.
[48]马增春,周思思,梁乾德,等.基于UPLC-TOF/MS分析人参附子配伍减毒的物质基础[J].药学学报,2011,46(12):1488-1492.
[49]王晓丽,李丽静,李玉梅,等.附子与人参不同配伍对心肌细胞的减毒作用[J].中国实验方剂学杂志,2015,21(11):153-158.
[2]Ameri A.The effects of aconitum alkaloids on the central nervous system[J].Progress in Neurobiology,1998,56(2):211-235.
[3]Omura T.Forty years of cytochrome P450[J].Biochemical and Biophysical Research Communications,1999,266(3):690-698.
[4]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.
[5]Axel M,Dagmar S,Peter HR,et al.Expression and inducibility of cytochrome P450 3A9(CYP3A9)and other members of the CYP3A subfamily in rat liver[J].Archives of Biochemistry and Biophysics,1997,337(1):1-7.
[6]Kiyoshi N,Makoto O,Miki S,et al.Structure and expression of the rat CYP3A1 gene:isolation of the gene(P450/6βB)and characterization of the recombinant protein[J].Archives of Biochemistry and Biophysics,1999,362(2):242-253.
[7]Lan T,Ling Y,Chang L,et al.Involvement of CYP3A4/5and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes[J].Toxicology Letters,2011,202(1):47-54.
[8]Ling Y,Tao W,Yang CH,et al.Microsomal cytochrome P450-mediated metabolism of hypaconitine,an active and highly toxic constituent derived from Aconitum species[J].Toxicology Letters,2011,204(1):81-91.
[9]Ling Y,Lan T,Yun G,et al.Characterization of metabolites and human P450 isoforms involved in the microsomal metabolism of mesaconitine[J].Xenobiotica,2011,41(1):46-58.
[10]Wang YG,Wang SQ,Liu YX,et al.Characterization of metabolites and cytochrome P450 isoforms involved in the microsomal metabolism of aconitine[J].Journal of Chromatography B,2006,844(2):292-300.
[11]毕云枫,刘舒,张瑞兴,等.UPLC-MS/MS方法研究中乌头碱的大鼠CYP450代谢产物及途径[J].药学学报,2013,48(12):1823-1828.
[12]毕云枫,李雪,皮子凤,等.UPLC-MS/MS方法研究次乌头碱在大鼠肝微粒体CYP450中的体外代谢产物及代谢酶亚型[J].质谱学报,2013,34(6):330-337.
[13]李晗,王宇光,马增春,等.乌头碱、新乌头碱和次乌头碱对CYP3A4抑制作用研究[J].中国新药杂志,2017,26(9):999-1004.
[14]Shou MG,Lu T,Kristopher WK,et al.Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism[J].European Journal of Pharmacology,2000,394(2):199-209.
[15]Zhu LJ,Yang XS,Zhou J,et al.The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultraperformance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone[J].Food and Chemical Toxicology,2013,51:396-403.
[16]Wu JJ,Cheng ZX,Zhu LJ,et al.Coadministration of Pinellia ternata Can signifcantly reduce aconitum carmi-chaelii to inhibit CYP3A Activity in Rats[J].Evidence-Based Complementary and Alternative Medicine,2014:1-10.
[17]Xiao Y,Ma ZC,Wang YG,et al.Cardioprotection of Shenfu preparata on cardiac myocytes through cytochrome P450[J].Journal of Integrative Medicine,2013,11(5):327-336.
[18]Skrupskii Va,Plaksin SE.Changes in the fatty acid composition of the phospholipids in the internal organs of rats during the modelling of aconitine arrhythmia[J].Eksp Klin Farmakol,1994,57(4):53-55.
[19]张琦,张大方.乌头类生物碱对慢性心衰大鼠心肌SOD活性和MDA含量的影响[J].时珍国医国药,2010,21(11):2812-2813.
[20]Gao XT,Zhang XC,Hu J,et al.Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria mediated pathway[J].Molecular Medicine Reports,2018,17(1):284-292.
[21]Ding F,Shao ZW,Yang SH,et al.Role of mitochondrial pathway in compression-induced apoptosis of nucleus pulposus cells[J].Apoptosis,2012,17:579-590.
[22]梁先敏.Caspase和JNK/SAPK、p38 MAPK与细胞凋亡[J].国外医学卫生学分册,2008,35(1):5-10.
[23]Sun GB,Sun H,Meng XB,et al.Aconitine-induced Ca2+overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats[J].Toxicology and Applied Pharmacology,2014,279(1):8-22.
[24]Alexander Db,Goldberg-GS.Transfer of biologically important molecules between cells through gap junction channals[J].Curr Med Chem,2003,10(19):2045-2058.
[25]Goran S,Klaus W.Gap junctions and the connexin protein family[J].Cardiovascular Research,2004,62(2):228-232.
[26]Stephan BD,Liu FY,Zhang J,et al.Modulation of cardiac gap junction expression and arrhythmic susceptibility[J].Circ Res,2004,95(10):1035-1041.
[27]Zhang SW,Liu Y,Huang GZ,et al.Aconitine alters connexin43 phosphorylation status and[Ca2+]oscillation patterns in cultured ventricular myocytes of neonatal rats[J].Toxicology in Vitro,2007,21(8):1476-1485.
[28]李志勇,谭鹏,孙建宁,等.次乌头碱对乳大鼠原代培养心肌细胞Ca2+及Cx43表达的影响[J].时珍国医国药,2011,22(11):2689-2691.
[29]Rao S,Sikdar-SK.Modification of alpha subunit of RIIA sodium channels by aconitine[J].Pflugers Arch,2000,439(3):349-355.
[30]Wright SN.Comparison of aconitine-modified human heart(h H1)and rat skeletal(1)muscle Na+channels:an important role for external Na+ions[J].Journal of Physiology,2002,538(3):759-771.
[31]Wang SY,Wang GK.Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins[J].Cellular Signalling,2003,15(2):151-159.
[32]龚冬梅,单宏丽,周宇宏,等.哇巴因和乌头碱诱发豚鼠和大鼠心律失常的离子作用靶点[J].药学学报,2004,39(5):328-332.
[33]董晞,赵世萍,刘岩,等.甘草苷对乌头碱致心肌细胞损伤的保护作用[J].中华中医药杂志,2009,24(2):163-166.
[34]Wang YJ,Chen BS,Lin MW,et al.Time-dependent block of ultrarapid-delayed rectier K1 currents by aconitine,a potent cardiotoxin,in heart-derived H9c2 myoblasts and in neonatal rat ventricular myocytes[J].Toxicological Sciences,2008,106(2):454-463.
[35]Ole HP,Michalak M,Verkhratsky A.Calcium signalling:Past,present and future[J].Cell Calcium,2005,38(3):161-169.
[36]李志勇,谭鹏,赵晖,等.次乌头碱对心肌细胞Ca2+调控蛋白m RNA表达的影响[J].重庆医学,2011,40(25):2546-2548.
[37]Geoffrey SP,Roger DZ,Andy H,et al.Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of Ltype Ca2+channels[J].The Journal of Biological Chemistry,2001,276(33):30794-30802.
[38]Fabien B,Jerome L,Le Guennec J,et al.Ca2+currents in cardiac myocytes:Old story,new insights[J].Progress in Biophysics and Molecular Biology,2006,91:1-82.
[39]Zhou YH,Piao XM,Liu X,et al.Arrhythmogenesis toxicity of aconitine is related to intracellular Ca2+signals[J].International Journal of Medical Sciences,2013,10(9):1242-1249.
[40]Wu JJ,Wang XC,Chung YY,et al.L-Type calcium channel inhibition contributes to the proarrhythmic effects of aconitine in human cardiomyocytes[J].Plos one,2017,12(1):1-18.
[41]Fu M,Wu M,Wang JF,et al.Disruption of the intracellular Ca2+homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes[J].Biochemical and Biophysical Research Communications,2007,354(4):929-936.
[42]沈少华,张宇燕,杨洁红,等.附子甘草配伍与炮制对乌头碱含量影响的比较研究[J].中华中医药学刊,2009,27(2):367-369.
[43]Wu JJ,Cheng ZX,Chen H,et al.The significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction The necessity of combination therapy of radix Aconiti[J].Journal of Ethnopharmacology,2015,170(1):251-254.
[44]周天梅,杨洁红,万海同,等.附子甘草主要成分配伍对乌头碱致大鼠传代心肌细胞损伤的保护作用[J].北京中医药大学学报,2014,37(1):22-27.
[45]刘巧云,张宇燕,万海同,等.甘草苷、甘草次酸与次乌头碱配伍的研究[J].中华中医药学刊,2013,31(3):493-495.
[46]Zhang YY,Yu L,Jin WF,et al.Reducing toxicity and increasing efficiency aconitine with liquiritin and glycyrrhetinic acid regulate calcium regulatory proteins in rat myocardial cell[J].Afr J Tradit Complement Altern Med,2017,14(4):69-79.
[47]董晞,赵世萍,刘岩,等.甘草苷对乌头碱致心肌细胞损伤的保护作用[J].中华中医药杂志,2009,24(2):163-166.
[48]马增春,周思思,梁乾德,等.基于UPLC-TOF/MS分析人参附子配伍减毒的物质基础[J].药学学报,2011,46(12):1488-1492.
[49]王晓丽,李丽静,李玉梅,等.附子与人参不同配伍对心肌细胞的减毒作用[J].中国实验方剂学杂志,2015,21(11):153-158.