Molecular Aspects of Microcystin-induced Hepatotoxicity and Hepatocarcinogenesis

REFERENCES

• Chorus , I and Bartram , J . 1999 . Toxic cyanobacteria in water. A guide to their public health consequences, monitoring and management , London : WHO .
   Google Scholar
• Yoshida , T , Takeda , M , Tsutsumi , T , Nagata , S , Yoshida , F , Maita , K , Harada , T and Ueno , Y . 2001 . Tumor necrosis factor-α expression and kupffer cell activation in hepatotoxicity caused by microcystin-LR in mice . J Toxicol Pathol , 14 ( 4 ) : 259
   Google Scholar
• Yu , S J . 1995 . Primary prevention of hepatocellular carcinoma . Journal of Gastroenterology and Hepatology. , 10 : 674 – 682 .
   PubMed Web of Science ®Google Scholar
• Ueno , Y , Nagatai , S , Tsutsumi , T , Hasegawa , A , Watanabe , M , Park , H , Chen , G , Chen , G and Yu , S . 1996 . Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay . Carcinogenesis. , 17 ( 6 ) : 1317 – 1321 .
   PubMed Web of Science ®Google Scholar
• Svirčev , Z , Krstić , S , Miladinov-Mikov , M , Baltić , V and Vidović , M. 2009 . Freshwater cyanobacterial blooms and primary liver cancer epidemiological studies in Serbia . J. Environ. Science Health, Part C , 27 ( 1 ) : 36 – 55 .
   Web of Science ®Google Scholar
• Yu , S , Zhao , N and Zi , X . 2001 . The relationship between cyanotoxin (microcystin, MC) in pond-ditch water and primary liver cancer in China . Zhonghua Zhong Liu Za Zhi , 23 ( 2 ) : 96 – 99 .
   PubMedGoogle Scholar
• Sekijima , M , Tsutsumi , T , Yoshida , T , Harada , T , Tashiro , F , Chen , G , Yu , S Z and Ueno , Y . 1999 . Enhancement of glutathione S-transferase placental-form positive liver cell foci development by microcystin-LR in aflatoxin B1-initiated rats . Carcinogenesis , 20 ( 1 ) : 161 – 165 .
   PubMed Web of Science ®Google Scholar
• McGlynn , K A , Tsao , L , Hsing , A W , Devesa , S S and Fraumeni , J F . 2001 . International trends and patterns of primary liver cancer . Intl J Cancer , 94 : 290 – 296 .
   PubMed Web of Science ®Google Scholar
• Hu , Z , Chen , H , Li , Y , Gao , L and Sun , C . 2002 . The expression of bcl-2 and bax genes during microcystin induced liver tumorigenesis . Zhonghua Yu Fang Yi Xue Za Zhi , 36 ( 4 ) : 239 – 242 .
   PubMedGoogle Scholar
• Weng , D , Lu , Y , Wei , Y , Liu , Y and Shen , P . 2007 . The role of ROS in microcystin-LR-induced hepatocyte apoptosis and liver injury in mice . Toxicology , 232 ( 1–2 ) : 15 – 23 .
   PubMed Web of Science ®Google Scholar
• Humpage , A R , Hardy , S J , Moore , E J , Froscio , S M and Falconer , I R . 2000 . Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon . J. Toxicol. Environ. Health, Part A , 61 ( 3 ) : 155 – 165 .
   PubMed Web of Science ®Google Scholar
• Žegura , B , Volčič , M , Lah , T T and Filipič , M. 2008 . Different sensitivities of human colon adenocarcinoma (CaCo-2), astrocytoma (IPDDC-A2) and lymphoblastoid (NCNC) cell lines to microcystin-LR induced reactive oxygen species and DNA damage . Toxicon , 52 ( 3 ) : 518 – 525 .
   PubMed Web of Science ®Google Scholar
• Milutinović , A , Zorc-Plesković , R , Petrović , D , Zorc , M and Šuput , D . 2006 . Microcystin-LR Induces Alterations in Heart Muscle . Folia Biologica (Praha) , 52 : 116 – 118 .
   PubMed Web of Science ®Google Scholar
• Li , H , Xie , P , Li , G , Hao , L and Xiong , Q . 2009 . In vivo study on the effects of microcystin extracts on the expression profiles of proto-oncogenes (c-fos, c-jun and c-myc) in liver, kidney and testis of male Wistar rats injected i.v. with toxins . Toxicon , 53 ( 1 ) : 169 – 175 .
   PubMed Web of Science ®Google Scholar
• Nishiwaki-Matsushima , R , Ohta , T , Nishiwaki , S , Suganuma , M , Kohyama , K , Ishikawa , T , Carmichael , W W and Fujiki , H . 1992 . Liver tumour promotion by the cyanobacterial cyclic peptide toxin microcystin-LR . J. Cancer Res. Clin. Oncol , 118 : 420 – 424 .
   PubMed Web of Science ®Google Scholar
• Carmichael , W W . 1992 . A review: cyanobacteria secondary metabolites—the cyanotoxins . J. Applied Bacteriology , 72 : 445 – 459 .
   PubMedGoogle Scholar
• IARC . 2006 . Ingested nitrate and nitrite, and cyanobacterial peptide toxins. International Agency for Research on Cancer IARC monographs on the evaluation of carcinogenic risks to humans , Vol. 94 , Lyon : IARC .
   Google Scholar
• Ito , E , Kondo , F , Terao , K and Harada , K-I . 1997 . Neoplastic nodular formation in mouse liver induced by repeated intraperitoneal injections of microcystin-LR . Toxicon , 35 : 1453 – 1457 .
   PubMed Web of Science ®Google Scholar
• Ding , W X , Shen , H M , Zhu , H G , Lee , B L and Ong , C N . 1999 . Genotoxicity of microcystic cyanobacteria extract of a water source in China . Mutation Research , 442 ( 2 ) : 69 – 77 .
   PubMedGoogle Scholar
• Abdel-Hamid , N . 2009 . Update to risk factors for hepatocellular carcinoma . International J. Medicine Medical Sci , 1 ( 3 ) : 38 – 43 .
   Google Scholar
• Žegura , B , Zajc , I , Lah , T T and Filipič , M. 2008 . Patterns of microcystin-LR induced alteration of the expression of genes involved in response to DNA damage and apoptosis . Toxicon , 51 : 615 – 623 .
   PubMed Web of Science ®Google Scholar
• Dietrich , D and Hoeger , S . 2005 . Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): A reasonable or misguided approach? . Toxicol. Applied Pharmacol , 203 ( 3 ) : 273 – 289 .
   PubMed Web of Science ®Google Scholar
• WHO . 1998 . “ Cyanobacterial toxins: Microcystin-LR ” . In Guidelines for drinking-water quality, Addendum to Volume 2 , Geneva : World Health Organization .
   Google Scholar
• Rudolph-Böhner , S , Mierke , D F and Moroder , L . 1994 . Molecular structure of cyanobacterial tumour-promoting microcystins . FEBS Letters , 349 : 319 – 323 .
   PubMed Web of Science ®Google Scholar
• Annila , A , Lehtimäki , J , Manila , K , Eriksson , J E , Sivonen , K , Rantala , T T and Drakenberg , T . 1996 . Solution structure of nodularin an inhibitor of serine/threonine specific protein phosphatases . J. Biol. Chem , 271 ( 28 ) : 16695 – 16702 .
   PubMedGoogle Scholar
• Barford , D and Keller , J . 1994 . Co-crystallization of the catalytic subunit of the serine/threonine specific protein phosphatase 1 from human in complex with microcystin-LR . J. Molec. Biol , 235 : 763 – 766 .
   PubMedGoogle Scholar
• Goldberg , J , Huang , H B , Kwon , Y G , Greengard , P , Nairn , A C and Kuriyan , J . 1995 . Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1 . Nature , 376 : 745 – 753 .
   PubMed Web of Science ®Google Scholar
• Carmichael , W W , Beasley , V R , Bunner , D L , Eloff , J N , Falconer , I , Gorham , P , Harada , K I , Krishnamurthy , T , Yu , M J , Moore , R E , Rinehart , K , Runnegar , M , Skulberg , O M and Watanabe , M . 1988 . Naming of cyclic heptapeptide toxins of cyanobacteria (blue-green algae) . Toxicon , 26 : 971 – 973 .
   PubMed Web of Science ®Google Scholar
• Fewer , D P , Rouhiainen , L , Jokela , J , Wahlsten , M , Laakso , K , Wang , H and Sivonen , K . 2007 . Recurrent adenylation domain replacement in the microcystin synthetase gene cluster . BMC Evolutionary Biology , 7 : 183
   PubMedGoogle Scholar
• Nicholson , B C and Burch , M D . 2001 . Evaluation of analytical methods for detection quantification of cyanotoxins in relation to Australian drinking water guidelines , Australia : Cooperative Research Centre for Water Quality and Treatment, National Health and Medical Research Council of Australia . Available at http://www.nhmrc.gov.au/publications/synopses/_files/eh22.pdf(Oct 10, 2009)
   Google Scholar
• Li , X , Lin , Y , Seng , L and Lin , J . 2003 . Responses of antioxidant systems in the hepatocytes of common carp (Cyprinus carpio L.) to the toxicity of MC-LR . Toxicon , 42 ( 1 ) : 85 – 89 .
   PubMed Web of Science ®Google Scholar
• Brooks , W P and Codd , G A . 1987 . Distribution of Microcystis aeruginosa peptide toxin and interactions with hepatic microsomes in mice . Pharmacol. Toxicol , 60 ( 3 ) : 187 – 191 .
   PubMedGoogle Scholar
• Robinson , N A , Matson , C F and Pace , J G . 1991 . Association of microcystin-LR and its biotransformation product with a hepatic-cytosolic protein . J. Biochem. Toxicol , 6 : 171 – 180 .
   PubMedGoogle Scholar
• Kondo , F , Matsumoto , H , Jamada , S , Ishikawa , N , Ito , E , Nagata , S , Ueno , Y , Suzuki , M and Horada , K . 1996 . Detection and identification of metabolits of microcystins formed in vivo in mouse and rat livers . Chem. Res. Toxicol , 9 : 1355 – 1359 .
   PubMed Web of Science ®Google Scholar
• Gehringer , M M , Shepard , E G , Downing , T G , Wiegand , C and Nielan , B A . 2004 . An Investigation into the detoxication of microcystin LR by the glutathione pathway in Balb/C mice . Intl. J. Biochem. Cell Biol , 35 ( 5 ) : 931 – 934 .
   Google Scholar
• Robinson , N A , Pace , J G , Matson , C F , Miura , G A and Lawrence , W B . 1991 . Tissue distribution, excretion and hepatic biotransformation of microcystin-LR in mice . J. Pharmacol. Exp. Therap , 256 ( 1 ) : 176 – 182 .
   PubMedGoogle Scholar
• Ito , E , Takai , A , Kondo , F , Masui , H , Imanishi , S and Harada , K I . 2002 . Comparison of protein phosphatase inhibitory activity and apparent toxicity of microcystins and related compounds . Toxicon , 40 ( 7 ) : 1017 – 1025 .
   PubMed Web of Science ®Google Scholar
• Hamm-Alvarez , S F and Sheetz , M P . 1998 . Microtubule-dependent vesicle transport: Modulation of channel and transporter activity in liver and kidney . Physiolog. Reviews , 78 : 1109 – 1129 .
   PubMed Web of Science ®Google Scholar
• Corwin , E J . 2006 . Handbook of pathophysiology: Foundations of health & disease , Philadelphia : Lippincott Williams & Wilkins .
   Google Scholar
• Fu , W Y , Xu , L H and Yu , Y N . 2005 . Proteomic analyses of cellular response to microcystin in human amnion FL cells . J. Proteomic Res , 4 : 2207 – 2215 .
   PubMed Web of Science ®Google Scholar
• Hiraga , A and Tamura , S . 2000 . Protein phosphatase 2A is associated in an inactive state with microtubules through 2A-1- specific interaction with tubuline . Biochem J , 346 ( 2 ) : 433 – 439 .
   PubMedGoogle Scholar
• Kumar , V , Abbas , A K and Fausto , N . 2005 . Robins and Cortan pathologic basis of disease , Philadelphia : Elsevier Saunders .
   Google Scholar
• Runnegar , M T , Wei , X and Hamm-Alvarez , S F . 1999 . Increased protein phosphorylation of cytoplasmic dynein results in impaired motor function . Biochem J , 15 ( 342 ) : 1 – 6 .
   Google Scholar
• Falconer , I R and Yeung , S K . 1992 . Cytoskeletal changes in hepatocytes induced by Microcystis toxins and their relation to hyperphosphorylation of cell proteins . Chem.-Biol. Interactions , 81 : 181 – 196 .
   PubMed Web of Science ®Google Scholar
• Clark , S P , Davis , M A , Ryan , T P , Searfoss , G H and Hooser , S B . 2007 . Hepatic Gene Expression Changes in Mice Associated with Prolonged Sublethal Microcystin Exposure . Toxicologic Patholology , 35 ( 4 ) : 594 – 605 .
   PubMed Web of Science ®Google Scholar
• Ghosh , S , Khan , S A , Wickstrom , M and Beasley , V . 1995 . Effects of microcystin-LR on actin and the actin-associated proteins alpha- actinin and talin in hepatocytes . Natural Toxins , 3 ( 6 ) : 405 – 414 .
   PubMedGoogle Scholar
• McDermott , C M , Nho , C W , Howard , W and Holton , B . 1998 . The cyanobacterial toxin, microcystin-LR, can induce apoptosis in a variety of cell types . Toxicon , 36 : 1981 – 1996 .
   PubMed Web of Science ®Google Scholar
• Chen , T , Wang , Q , Cui , J , Yang , W , Shi , Q , Hua , Z , Ji , J and Shen , P . 2005 . Induction of apoptosis in mouse liver by microcystin-LR: A combined transcriptomic, proteomic, and simulation strategy . Molec Cell Proteomics , 4 : 958 – 974 .
   PubMed Web of Science ®Google Scholar
• Mereish , K A , Bunner , D L , Ragland , D R and Creasia , D A . 1991 . Protection against microcystin-LR-induced hepatotoxicity by Silymarin: biochemistry, histopathology, and lethality . Pharmaceut Res , 8 ( 2 ) : 273 – 277 .
   PubMed Web of Science ®Google Scholar
• Lu , H , Choudhuri , S , Ogura , K , Csanaky , I L , Lei , X , Cheng , X , Song , P Z and Klaassen , C D . 2008 . Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR . Toxicol Sci , 103 ( 1 ) : 35 – 45 .
   PubMedGoogle Scholar
• Moreno , I , Pichardo , S , Jos , A , Gómez-Amores , L , Mate , A , Vazquez , C M and Cameán , A M . 2005 . Antioxidant enzyme activity and lipid peroxidation in liver and kidney of rats exposed to microcystin-LR administered intraperitoneally . Toxicon , 45 ( 4 ) : 395 – 402 .
   PubMed Web of Science ®Google Scholar
• Billam , M . 2006 . Development and validation of microcystin biomarkers for exposure studies (dissertation) , Texas : Texas Tech University .
   Google Scholar
• Hooser , S B . 2000 . Fulminant hepatocyte apoptosis in vivo following microcystin-LR administration to rats . Toxicologic Pathology , 28 ( 5 ) : 726 – 733 .
   PubMed Web of Science ®Google Scholar
• Billam , M , Mukhi , S , Tanga , L , Gaoa , W and Wang , J S . 2008 . Toxic response indicators of microcystin-LR in F344 rats following a single-dose treatment . Toxicon , 51 : 1068 – 1080 .
   PubMedGoogle Scholar
• Ding , W X , Shen , H M and Ong , C N . 2000 . Microcystic cyanobacteria extract induces cytoskeletal disruption and intracellular glutathione alteration in hepatocytes . Environ. Health Persp , 108 ( 7 ) : 605 – 609 .
   PubMed Web of Science ®Google Scholar
• Sedmak , B and Šuput , D . 2002 . Co-operative effects in tumorigenicity. The microcystin example . Radiology & Oncology , 36 ( 2 ) : 162 – 164 .
   Google Scholar
• Leong , T Y and Leong , A S . 2005 . Epidemiology and carcinogenesis of hepatocellular carcinoma . HPB (Oxford) , 7 ( 1 ) : 5 – 15 .
   PubMedGoogle Scholar
• Fisher , W J , Altheimer , S , Cattori , V , Meier , P J , Dietrich , D R and Hagenbuch , B . 2005 . Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin . Toxicol. Applied Pharmacol , 203 ( 3 ) : 257 – 263 .
   PubMedGoogle Scholar
• Chen , T , Cui , J , Liang , Y , Xin , X , Young , D O , Chen , C and Shen , P . 2006 . Identification of human liver mitochondrial aldehyde dehydrogenase as a potential target for microcystin-LR . Toxicology , 220 ( 1 ) : 71 – 80 .
   PubMed Web of Science ®Google Scholar
• Holmes , C FB , Craig , M , McCready , T L , Boland , M P , Dawson , J F , Chen , D ZX , Wang , K , Klix , H Luu , H A . . Regulation of signal transduction pathways by peptide toxins . Proc 13th Am Pept Symp . Edited by: Hodges , R S and Smith , J A . pp. 577 – 579 . Leiden : ESCOM .
   Google Scholar
• Bagu , J R , Sykes , B , Craig , M and Holmes , C FB . 1997 . A molecular basis for different interactions of marine toxins with protein phosphatase 1 . J. Biol. Chem , 272 : 5087 – 5097 .
   PubMed Web of Science ®Google Scholar
• Mac Kintosh , R V , Dalby , K N , Campbell , D G , Choen , P T , Choen , P and Mac Kintosh , C . 1995 . The cyanobacterial toxin microcystin binds covalently to cisteine-273 on protein phosphatase—1 . FEBS Letters , 371 ( 3 ) : 236 – 240 .
   PubMedGoogle Scholar
• Favre , B , Turowski , P and Hemmings , B A . 1997 . Differential inhibition and posttranslational modification of protein phosphatase 1 and 2A in MCF7 cells treated with calyculin-A, okadaic acid, and tautomycin . J. Biol. Chem , 272 ( 21 ) : 13856 – 13863 .
   PubMed Web of Science ®Google Scholar
• Berndt , N . 1999 . Protein dephosphorylation and the intracellular control of the cell number . Frontiries in Bioscience , 4 : D22 – 42 .
   PubMedGoogle Scholar
• Garcia , A , Cayla , X , Guergnon , J , Dessauge , F , Hospital , V , Rebollo , M P , Fleischer , A and Rebollo , A . 2003 . Serine/threonine protein phosphatases PP-1 and PP-2A are key players in apoptosis . Biochimie , 85 ( 8 ) : 721 – 726 .
   PubMedGoogle Scholar
• Van Hoof , C and Goris , J . 2003 . Phosphatases in apoptosis: to be or not to be, PP-2A is in the heart of the question . Biochim. Biophys. Acta , 1640 ( 2–3 ) : 97 – 104 .
   PubMed Web of Science ®Google Scholar
• Honkanen , R E , Zwiller , J , Moore , R E , Daily , S L , Khatra , B S , Dukelow , M and Boynton , A L . 1990 . Characterization of microcystin- LR, a potent inhibitor of type 1 and type 2A protein phosphatases . J. Biol. Chem , 265 : 19401 – 19404 .
   PubMed Web of Science ®Google Scholar
• Runnegar , M TC , Kong , S M and Berndt , N . 1993 . Protein phosphatase inhibition and in vivo hepatotoxicity of microcystins . Am. J. Physiol , 265 ( 2 ) : G224 – G230 . part 1
   Google Scholar
• Wera , S and Hemmings , B A . 1995 . Serine/threonine protein phosphatases . Biochem. J , 311 ( 1 ) : 17 – 29 .
   PubMedGoogle Scholar
• Yamano , H , Ishii , K and Yanagida , M . 1994 . Phosphorylation of dis2 protein phosphatase at the C-terminal cdc2 consensus and its potential role in cell cycle regulation . EMBO J , 13 : 5310 – 5318 .
   PubMed Web of Science ®Google Scholar
• Cohen , P . 1989 . The structure and regulation of protein phosphatases . Ann. Rev. Biochem , 58 : 453 – 508 .
   PubMed Web of Science ®Google Scholar
• Li , H-H , Cai , X , Shouse , G P , Piluso , L G and Liu , X . 2007 . A specific PP2A regulatory subunit, B56, mediates DNA damage-induced dephosphorylation of p53 at Thr55 . EMBO J , 26 : 402 – 411 .
   PubMed Web of Science ®Google Scholar
• Ho , R , Choi , L , Lee , W , Mayo , G , Shwartz , U I and Tirona , R G . 2007 . Effect of drug transporter genotipes on pravastatin disposition in Europa—and Africa—American participants . Farmacogenet Genomics , 17 : 647 – 656 .
   PubMed Web of Science ®Google Scholar
• Zhang , W , He , Y J , Han , C T , Liu , Z Q , Li , Q and Fan , L . 2006 . Effect of SICO1B1 genetic polymorphism on the pharmacokinetics of nateglinide . Br. J. Clin. Pharmacol , 62 : 567 – 572 .
   PubMed Web of Science ®Google Scholar
• Niemi , M , Kvisto , K T , Hofmann , U , Shwab , M , Eichelbaumm , M and Fromm , M F . 2005 . Fexofenadine farmacokinetics are associated with a polymorphism of the SLOC1B1 gene (encoding OATP1B1) . Br. J. Clin. Pharmacol , 59 : 602 – 604 .
   PubMed Web of Science ®Google Scholar
• Ding , W X , Shen , H M and Ong , C N . 2001 . Pivotal role of mitochondrial Ca2 + in microcystine-induced mitochondrial permeability transition in rat hepatocytes. Biochem . Biophys. Res. Comm , 285 : 1155 – 1161 .
   PubMedGoogle Scholar
• Dürr , R and Caselmann , W H . 2000 . Carcinogenesis of primary liver malignancies . Langenbeck's Arch Surg , 385 : 154 – 161 .
   PubMed Web of Science ®Google Scholar
• Beasley , V . 1999 . “ Introduction to the Toxicology of the Liver ” . In Veterinary Toxicology , Edited by: Beasley , V . International Veterinary Information Service . Available from www.ivis.org
   Google Scholar
• Žegura , B , Sedmak , B and Filipič , M. 2003 . Microcystin-LR induces oxidative DNA damage in human hepatoma cell line HepG2 . Toxicon , 41 : 41 – 48 .
   PubMed Web of Science ®Google Scholar
• Serban , G , Kouchi , Z , Baki , L , Georgakopoulos , A , Litterst , C M , Shioi , J and Robakis , N K . 2005 . Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability . J. Biol. Chem , 280 ( 43 ) : 36007 – 36012 .
   PubMedGoogle Scholar
• Saffroy , R , Lemoine , A and Debuire , B . 2006 . Mechanisms of hepatocarcinogenesis . Atlas Genet Cytogenet Oncol Haematol , Available at http://AtlasGeneticsOncology.org/Deep/HepatocarcinogenesisID20055.html
   PubMedGoogle Scholar
• Bouaicha , N , Maatouk , I , Plessis , M J and Perin , F . 2005 . Genotoxic potential of Microcystin—LR and nodularin in vitro in primary cultured rat hepatocytes and in vivo in rat liver . Environ. Toxicol , 20 ( 3 ) : 341 – 347 .
   PubMed Web of Science ®Google Scholar
• Shen , C L , Song , W and Pence , B C . 2001 . Interactions of selenium compounds with other antioxidants in DNA damage and apoptosis in human normal keratinocytes . Cancer Epidemiology Biomarkers & Prevention , 10 ( 4 ) : 385 – 390 .
   PubMedGoogle Scholar
• Rao , P VL and Bhattacharya , R . 1996 . The cyanobacterial toxin microcystin-LR induced DNA damage in mouse liver in vivo . Toxicology , 114 : 29 – 36 .
   PubMed Web of Science ®Google Scholar
• Honma , M , Momose , M , Tanabe , H , Sakamoto , H , Yu , Y , Little , J B , Sofuni , T and Hayashi , M . 2000 . Requirement of wild-type p53 protein for maintenance of chromosomal integrity . Molecular Carcinogenesis , 28 ( 4 ) : 203 – 214 .
   PubMedGoogle Scholar
• Zan , L , Sakamoto , H , Sakuraba , M , Wu , D S , Zhang , L S , Suzuki , T , Hayashi , M and Honma , M . 2004 . Genotoxicity of microcystin-LR in human lymphoblastoid TK6 cells . Mutation Research , 557 ( 1 ) : 1 – 6 .
   PubMedGoogle Scholar
• Suzuki , H , Watanabe , M F , Wu , Y , Sugita , T , Kita , K , Sato , T , Wang , X L , Tanzawa , H , Sekiya , S and Suzuki , N . 1998 . Mutagenicity of microcystin-LR in human RSa cells . Intl. J. Molec. Med , 2 : 109 – 112 .
   PubMedGoogle Scholar
• Alvarca , E , Andrade , M , Dias , E , Sam Bento , F , Batoreu , M CC , Jordan , P , Silva , M J and Pereira , P . 2009 . Morphological and ultrastructural effect of MC-LR from Microcystins aeruginose extracts on a kidney cell line . Toxicon , 30 : 1 – 12 .
   Google Scholar
• Guzman , R E and Solter , P F . 2002 . Characterization of subletal MC-LR exposure in mice . Veterinary Pathology , 39 ( 1 ) : 17 – 26 .
   PubMedGoogle Scholar
• Andreeff , M , Goodrich , D W and Pardee , A B . 2000 . “ Cell proliferation, differentiation and apoptosis ” . In Cancer Medicine, , 5 ed. , Edited by: Holland , J F and Frei , E . 24 – 32 . London : B.C. Decker Inc, Hamilton .
   Google Scholar
• Tan , X W , Xia , H , Xu , J H and Cao , J G . 2009 . Induction of apoptosis in human liver Hep2 cell line by 5-acyl-7-gen-difluoromethilenechrysin . World J. Gastroenterology , 15 ( 18 ) : 2234 – 2239 .
   PubMedGoogle Scholar
• Wen-yu , F , Jia-ping , C , Xiu-min , W and Li-hong , X . 2005 . Altered expression of p53, Bcl-2 and Bax induced by microcystin-LR in vivo and in vitro . Toxicon , 46 ( 2 ) : 171 – 177 .
   PubMedGoogle Scholar
• Falconer , Y . 2005 . Cyanobacterial toxins of drinking water supplies. Cylindrospermopsin and microcystin , Boca Raton, Florida : CRC Press .
   Google Scholar
• Humpage , A R and Falconer , I R . 1999 . Microcystin-LR and liver tumor promotion: effects on cytokinesis, ploidy, and apoptosis in cultured hepatocytes . Environ. Toxicol , 14 : 61 – 75 .
   Web of Science ®Google Scholar
• Cinique , B , DiMarizio , L , Centi , C , DiRocco , C , Riccardi , C and Graziacifone , M . 2003 . Sphingolipids and the immune system . Pharmacol. Res , 47 ( 5 ) : 421 – 437 .
   PubMedGoogle Scholar
• Chiang , C W , Harris , G , Ellig , C , Masters , S C , Subramanian , R and Shenolikar , S . 2001 . Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation . Blood , 97 : 1289 – 1297 .
   PubMed Web of Science ®Google Scholar
• Wang , J , Lv , X , Shi , J and Hu , X . 2006 . Ceramide induces apoptosis via a peroxisome proliferator activated receptor -γ -dependent pathway . Apoptosis , 11 : 2043 – 2045 .
   PubMedGoogle Scholar
• Falconer , I R , Burch , M D , Steffensen , D A , Choice , M and Coverdale , O R . 1994 . Toxicity of the blue-green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs, as an animal model for human injury and risk assessment . Enviro. Toxicol. Water Quality , 9 : 131 – 139 .
   Google Scholar
• Gehringer , M M . 2004 . Microcystin-LR and okadaic acid-induced cellular effects: a dualistic response . FEBS Letters , 557 : 1 – 8 .
   PubMed Web of Science ®Google Scholar
• Toivola , D M and Eriksson , J E . 1999 . Toxins affecting cell signaling alter cytoskeletal structure . Toxicology In Vitro , 13 : 521 – 530 .
   PubMedGoogle Scholar
• Deng , X , Ito , T , Carr , B , Mumby , M and May , W S Jr . 1998 . Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A . J. Biol. Chem , 273 ( 51 ) : 34157 – 34163 .
   PubMedGoogle Scholar
• Nishizuka , Y . 1992 . Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C . Science , 258 : 607 – 614 .
   PubMed Web of Science ®Google Scholar
• Komatsu , M , Furukawa , T , Ikeda , R , Takumi , S , Nong , Q , Aoyama , K , Akiyama , S , Keppler , D and Takeuchi , T . 2007 . Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3 . Toxicol. Sci , 97 ( 2 ) : 407 – 416 .
   PubMedGoogle Scholar
• Wei , Y , Weng , D , Li , F , Zou , X , Young , D O , Ji , J and Shen , P . 2008 . Involvement of JNK regulation in oxidative stress-mediated murine liver in JURY by Microcystine-LR . Apoptosis , 13 : 1031 – 1042 .
   PubMed Web of Science ®Google Scholar
• Lankoff , A , Bialczyk , J , Dziga , D , Carmichael , W W , Gradzka , I , Lisowska , H , Kuszewski , T , Gozdz , S , Piorun , I and Wojcik , A . 2006 . The repair of gamma-radiation-induced DNA damage is inhibited by microcystin-LR, the PP-1 and PP-2A phosphatase inhibitor . Mutagenesis , 21 ( 1 ) : 83 – 90 .
   PubMed Web of Science ®Google Scholar
• Clark , S P , Ryan , T P , Searfoss , G H , Davis , M A and Hooser , S B . 2008 . Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and cyclin-associated genes in P53-deficient mice . Toxicologic Pathology , 36 ( 2 ) : 190 – 203 .
   PubMedGoogle Scholar
• Fujiki , H and Suganuma , M . 1993 . Tumor promotion by inhibitors of protein phosphatases 1 and 2A: the okadaic acid class of compounds . Adv. Cancer Res , 61 : 143 – 194 .
   PubMed Web of Science ®Google Scholar
• Milczarek , G J , Chen , W , Gupta , A , Martinez , J D and Bowden , T . 1999 . Okadaic acid mediates p53 hyperphosphorylation and growth arrest in cells with wild-type p53 but increases aberrant mitoses in cells with non-functional p53 . Carcinogenesis , 20 ( 6 ) : 1043 – 1048 .
   PubMedGoogle Scholar
• Markovics , J A . 1999 . The roles of the Rb and p53 tumor suppressor pathways in an intestinal tumorigenesis model system (dissertation) , Pittsburgh, , USA : University of Pittsburgh .
   Google Scholar
• Hu , Z , Chen , H , Pang , C and Lin , Q . 2008 . The expression of p53 and p16 in the course of microcystin-LR inducing of liver tumor . The Chinese-German Journal of Clinical Oncology , 7 ( 12 ) : 690 – 693 .
   Google Scholar
• Maximov , G K and Maximov , K G . 2008 . The role of p53 tumor-suppressor protein in apoptosis and cancerogenesis . Biotechnology & Biotechnological Equipment , : 664 – 668 .
   Google Scholar