Pyrrolizidine alkaloids: Potential role in the etiology of cancers, pulmonary hypertension, congenital anomalies, and liver disease

Chemical Research in Toxicology

Volumn 28, Issue 1, 2015, Pages 4-20

  Edgar, John A ^a   Molyneux, Russell J ^b   Colegate, Steven M ^c  

^a CSIRO   (Australia)

^b UNIVERSITY OF HAWAII AT HILO   (United States)

^c AGRICULTURAL RESEARCH SERVICE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2-DEHYDROPYRROLIZIDINE ALKALOID; PYRROLIZIDINE ALKALOID; UNCLASSIFIED DRUG;

ACUTE TOXICITY; CARCINOGENESIS; CHRONIC TOXICITY; CONGENITAL MALFORMATION; FOOD POISONING; GENOTOXICITY; LIVER DISEASE; LIVER VENOOCCLUSIVE DISEASE; NEOPLASM; NONHUMAN; PULMONARY HYPERTENSION; REVIEW; TERATOGENICITY; ANIMAL; CHEMICALLY INDUCED; CONGENITAL ABNORMALITIES; DRUG-INDUCED LIVER INJURY; FOOD CONTAMINATION; HUMAN;

ANIMALS; CONGENITAL ABNORMALITIES; DRUG-INDUCED LIVER INJURY; FOOD CONTAMINATION; HUMANS; HYPERTENSION, PULMONARY; NEOPLASMS; PYRROLIZIDINE ALKALOIDS;

EID: 84922426811     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx500403t     Document Type: Review

References (262)

1. Willmot, F. C. and Robertson, G. W. (1920) Senecio disease, or cirrhosis of the liver due to Senecio poisoning Lancet 848-849
2. Steyn, D. G. (1933) Poisoning of human beings by weeds contained in cereals (Bread Poisoning) Onderstepoort J. Vet. Sci. Anim. Ind. 1, 219-266
3. Selzer, G. and Parker, R. G. F. (1951) Senecio poisoning as Chiari's syndrome. A report on twelve cases Am. J. Pathol. 27, 885-907
4. Bull, L. B., Culvenor, C. C. J., and Dick, A. J. (1968) The Pyrrolizidine Alkaloids. Their Chemistry, Pathogenicity and Other Biological Properties, North Holland Publishing Co., Amsterdam, The Netherlands.
5. Tandon, B. N., Tandon, R. K., Tandon, H. D., Narndranathan, M., and Joshi, Y. K. (1976) An epidemic of veno-occlusive disease of liver in central India Lancet 2, 271-272
6. Tandon, R. K., Tandon, B. N., Tandon, H. D., Bhatia, M. L., Bhargava, S., Lal, P., and Arora, R. R. (1976) Study of an epidemic of venoocclusive disease in India Gut 17, 849-855
7. Mohabbat, O., Younos, M. S., Merzad, A. A., Srivastava, R. N., Sediq, G. G., and Aram, G. N. (1976) An outbreak of hepatic veno-occlusive disease in North-Western Afghanistan Lancet 308, 269-271
8. International Programme on Chemical Safety (IPCS) (1988) Pyrrolizidine alkaloids: Environmental Health Criteria 80, WHO, Geneva, Switzerland, www.inchem.org/documents/ehc/ehc/ehc080.htm.
9. International Programme on Chemical Safety (IPCS) (1989) Pyrrolizidine alkaloids: health and safety guide no. 26; WHO, Geneva, Switzerland, http://www.inchem.org/documents/hsg/hsg/hsg026.htm.
10. Chauvin, P., Dillon, J., Moren, A., Talbak, S., and Barakaev, S. (1993) Heliotrope poisoning in Tadjikistan Lancet 341, 1663
11. Chauvin, P., Dillon, J. C., and Moren, A. (1994) An outbreak of heliotrope food poisoning, Tadjikistan, November 1992-March 1993 Sante 4, 263-268
12. Mayer, F. and Lüthy, J. (1993) Heliotrope poisoning in Tadjikistan Lancet 342, 246-247
13. Altaee, M. Y. and Mahmood, M. H. (1998) An outbreak of veno-occlusive disease of the liver in northern Iraq East. Mediterr. Health J. 4, 142-148
14. Integrated Regional Information Networks (IRIN) (2008) Afghanistan: "Charmak" disease still killing people, livestock in west, UN Office for the Coordination of Humanitarian Affairs, http://www.irinnews.org/Report.aspx?ReportId=81971.
15. Kleiman, R., Rentz, E. D., Teshale, E., Thompson, N., and Schurz-Rogers, H. (2008) Update on research and activities at the Centers for Disease Control and Prevention, and the Agency for Toxic Substances and Disease Registry J. Med. Toxicol. 4, 197-200
16. Kakar, F., Akbarian, Z., Leslie, T., Mustafa, M. L., Watson, J., van Egmond, H. P., Omar, M. F., and Mofleh, J. (2010) An outbreak of hepatic veno-occlusive disease in western Afghanistan associated with exposure to wheat flour contaminated with pyrrolizidine alkaloids J. Toxicol. 2010, 313280
17. Edgar, J. A. (2003) Pyrrolizidine alkaloids and food safety Chem. Aust. 70, 4-7
18. Food Standards Australia New Zealand (FSANZ) (2001) Pyrrolizidine alkaloids in food. A toxicological review and risk assessment, Tech. Report series No. 2, FSANZ, Canberra, Australia, http://www.foodstandards.gov.au/publications/documents/TR2.pdf.
19. Azadbakht, M. and Talavaki, M. (2003) Qualitative and quantitative determination of pyrrolizidine alkaloids of wheat and flour contaminated with Senecio in Mazandaran Province farms Iran. J. Pharm. Res. 2, 179-183
20. Edgar, J. A., Colegate, S. M., Boppré, M., and Molyneux, R. J. (2011) Pyrrolizidine alkaloids in food: a spectrum of potential health consequences Food Addit. Contam. 28, 308-324
21. Bodi, D., Ronczka, S., Gottschalk, C., Behr, N., Skibba, A., Wagner, M., Lahrssen-Wiederholt, M., Preiss-Weigert, A., and These, A. (2014) Determination of pyrrolizidine alkaloids in tea, herbal drugs and honey Food Addit. Contam. 31, 1886-1895
22. Dickinson, J. O. and King, R. R. (1978) The transfer of pyrrolizidine alkaloids from Senecio jacobaea into milk of lactating cows and goats, in Effects of Poisonous Plants on Livestock (Keeler, I., VanKampen, K. R., and James, L. F., Eds.) pp 201-206, Academic Press, New York.
23. Deinzer, M. L., Thomson, P. A., Burgett, D. M., and Isaacson, D. L. (1977) Pyrrolizidine alkaloids: their occurrence in honey from tansy ragwort (Senecio jacobaea L.) Science 195, 497-499
24. Culvenor, C. C. J., Edgar, J. A., and Smith, L. W. (1981) Pyrrolizidine alkaloids in honey from Echium plantagineum L J. Agric. Food Chem. 29, 958-960
25. 3H]pyrrolizidine alkaloids from Senecio vulgaris L. and metabolites into rat milk and tissues Toxicol. Lett. 17, 283-288
26. Molyneux, R. J. and James, L. F. (1990) Pyrrolizidine alkaloids in milk: thresholds of in toxication Vet. Hum. Toxicol. 32 (Suppl.) 94S-103S
27. Edgar, J. A. and Smith, L. W. (2000) Transfer of pyrrolizidine alkaloids into eggs: food safety implications, in Natural and Selected Synthetic Toxins, Biological Implications. (Tu, A. T. and Gaffield, W., Eds.) ACS Symposium Series 745, Chapter 8, pp 118-128, American Chemical Society, Washington, DC.
28. Beales, K. A., Betteridge, K., Colegate, S. M., and Edgar, J. A. (2004) Solid phase extraction and LCMS analysis of pyrrolizidine alkaloids in honeys J. Agric. Food Chem. 52, 6664-6672
29. Beales, K, Betteridge, K, Boppré, M, Cao, Y, Colegate, S. M., and Edgar, J. A. (2007) Hepatotoxic pyrrolizidine alkaloids and their N -oxides in honey and pollen, in Poisonous Plants: Global Research and Solutions (Panter, K., Wierenga, T., and Pfister, J., Eds.) Chapter 16, pp 94-100, CABI, Wallingford.
30. Bundesamt für Risiokobewertung (BfR) (2007) Salatmischung mit pyrrolizidinalkaloid-haltigem Greiskraut verunreinigt, Stellungnahme Nr.028/2007 des BfR vom 10, http://www.bfr.bund.de/cm/208/salatmischung-mit-pyrrolizidinalkaloid-haltigem-geiskraut-verunreinigt.pdf.
31. Bundesamt für Risiokobewertung (BfR) (2011) Chemical analysis and toxicity of pyrrolizidine alkaloids and assessment of the health risk posed by their occurrence in honey, BfR opinion no. 038/2011 11, http://www.bfr.bund.de/cm/349/chemical-analysis-and-toxicity-of-pyrrolizidine-alkaloids-and-assessment-of-the-health-risks-posed-by-their-occurence-in-honey.pdf.
32. Bundesamt für Risiokobewertung (BfR) (2013) Pyrrolizidine alkaloids in herbal teas and teas, BfR opinion no. 018/2013, http://www.bfr.bund.de/cm/349/pyrrolizidine-alkaloids-in-herbal-teas-and-teas.pdf.
33. Kempf, M., Heil, S., Hasslauer, I., Schmidt, L., von der Ohe, K., Theuring, C., Reinhard, A., Scheier, P., and Beuerle, T. (2010) Pyrrolizidine alkaloids in pollen and pollen products Mol. Nutr. Food Res. 54, 1-9
34. Hoogenboom, L. A. P., Mulder, P. P. J., Zeilmaker, M. J., van den Top, H. J., Remmelink, G. J., Brandon, E. F. A., Klijnstra, M., Meijer, G. A. L., Schothorst, R., and van Egmond, H. P. (2011) Carry-over of pyrrolizidine alkaloids from feed in dairy cows Food Addit. Contam. 28, 359-372
35. Dübecke, A., Beckh, G., and Lüllmann, C. (2011) Pyrrolizidine alkaloids in honey and bee pollen Food Addit. Contam. 28, 348-358
36. Fletcher, M. T., McKenzie, R. A., Reichmann, K. G., and Blaney, B. J. (2011) Risks from plants containing pyrrolizidine alkaloids for livestock and meat quality in northern Australia, in Poisonings by Plants, Mycotoxins and Related Toxins (Riet-Correa, F., Pfister, J., Schild, A. L., and Wierenga, T., Eds.) pp 208-218, CAB International, Wallingford, UK.
37. Kempf, M., Wittig, M., Schönfeld, K., Cramer, L., Schreier, P., and Beuerle, T. (2011) Pyrrolizidine alkaloids in food: downstream contamination in the food chain caused by honey and pollen Food Addit. Contam. 28, 325-331
38. Kempf, M., Wittig, M., Reinhard, A., von der Ohe, K., Blacquiére, T., Raezke, K.-P., Michel, R., Scheier, P., and Beuerle, T. (2011) Pyrrolizidine alkaloids in honey: comparison of analytical methods Food Addit. Contam. 28, 332-347
39. Cao, Y., Colegate, S. M., and Edgar, J. A. (2013) Persistence of echimidine, a hepatotoxic pyrrolizidine alkaloid, from honey into mead J. Food Compos. Anal. 29, 106-109
40. Griffin, C. T., Danaher, M., Elliott, C. T., Kennedy, D. G., and Furey, A. (2013) Detection of pyrrolizidine alkaloids in commercial honey using liquid chromatography-ion trap mass spectrometry Food Chem. 136, 1577-1583
41. Edgar, J. A., Roeder, E., and Molyneux, R. J. (2002) Honey from plants containing pyrrolizidine alkaloids: a potential threat to health J. Agric. Food Chem. 50, 2719-2730
42. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) (2008) COT statement on pyrrolizidine alkaloids in food, http://cot.food.gov.uk/pdfs/cotstatementpa200806.pdf.
43. WHO (2011) Discussion paper on pyrrolizidine alkaloids, Joint FAO/WHO food standards programme, Codex committee on contaminants in foods, 5th session, The Hague, The Netherlands, 21-25 March, ftp://ftp.fao.org/codex/meetings/cccf/cccf5/cf05-14e.pdf.
44. European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain (CONTAM) (2011) Scientific opinion on pyrrolizidine alkaloids in food and feed EFSA J. 9, 2406-2540
45. The U.S. National Toxicology Program (2011) 12th Report on Carcinogens (RoC), pp iii-499, U.S. Department of Health and Human Services, Washington, DC.
46. Chen, T., Mei, N., and Fu, P. P. (2010) Genotoxicity of pyrrolizidine alkaloids J. Appl. Toxicol. 30, 183-196
47. Edgar, J. A. (2014) Food contaminants capable of causing cancer, pulmonary hypertension and cirrhosis Med. J. Aust. 200, 73-74
48. Green, C. R. and Christie, G. S. (1961) Malformation in foetal rats induced by the pyrrolizidine alkaloid, heliotrine Br. J. Exp. Pathol. 42, 369-378
49. Peterson, J. E. and Jago, M. V. (1980) Comparison of the toxic effects of dehydroheliotridine and heliotrine in pregnant rats and their embryos J. Pathol. 131, 339-355
50. Smith, L. W. and Culvenor, C. C. J. (1981) Plant sources of hepatotoxic pyrrolizidine alkaloids J. Nat. Prod. 44, 129-152
51. Reimann, A., Nurhayati, N., Backenköhler, A., and Ober, D. (2004) Repeated evolution of the pyrrolizidine alkaloid-mediated defense system in separate angiosperm lineages Plant Cell 16, 2772-2784
52. Mattocks, A. R. (1986) Chemistry and Toxicology of Pyrrolizidine Alkaloids, Academic Press, London, UK.
53. Mattocks, A. R. (1968) Toxicity of pyrrolizidine alkaloids Nature 217, 723-728
54. Culvenor, C. C. J., Downing, D. T., Edgar, J. A., and Jago, M. V. (1969) Pyrrolizidine alkaloids as alkylating and antimitotic agents Ann. N.Y. Acad. Sci. 163, 837-847
55. Jago, M. V., Edgar, J. A., Smith, L. W., and Culvenor, C. C. J. (1970) Metabolic conversion of heliotridine-based pyrrolizidine alkaloids to dehydroheliotridine Mol. Pharmacol. 6, 402-406
56. Butler, W. H., Mattocks, A. R., and Barnes, J. M. (1970) Lesions in the liver and lungs of rats given pyrrole derivatives of pyrrolizidine alkaloids J. Pathol. 100, 169-175
57. Williams, D. E., Reed, R. L., Kedzierski, B., Dannan, G. A., Guengerich, F. P., and Buhler, D. R. (1989) Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver Drug Metab. Dispos. 17, 387-392
58. Miranda, C. L., Reed, R. L., Guengerich, F. P., and Buhler, D. R. (1991) Role of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver Carcinogenesis 12, 515-519
59. Hincks, J. R., Kim, H.-Y., Segall, H. J., Molyneux, R. J., Stermitz, F. R., and Coulombe, R. A. (1991) DNA cross-linking in mammalian cells by pyrrolizidine alkaloids: structure-activity relationships Toxicol. Appl. Pharmacol. 111, 90-98
60. Chung, W. G. and Buhler, D. R. (1994) The effect of spironolactone treatment on the cytochrom P450-mediated metabolism of the pyrrolizidine alkaloid senecionine by hepatic microsomes from rats and guinea pigs Toxicol. Appl. Pharmacol. 127, 314-319
61. Chung, W. G., Miranda, C. L., and Buhler, D. R. (1995) A cytochrome P450B form is the major bioactivation enzyme for the pyrrolizidine alkaloid senecionine in guinea pig Xenobiotica 25, 929-939
62. Kim, H.-Y., Stermitz, F. R., and Coulombe, R. A. (1995) Pyrrolizidine alkaloid-induced DNA-protein cross-links Carcinogenesis 16, 2691-2697
63. Kasahara, Y., Kiyatake, K., Tatsumi, K., Sugito, K., Kakusaka, I., Yamagata, S., Ohmori, S., Kitada, M., and Kuriyama, T. (1997) Bioactivation of monocrotaline by P450 3A in rat liver J. Cardiovasc. Pharmacol. 30, 124-129
64. 14C-monocrotaline in rat liver microsomes J. Biochem. Mol. Toxicol. 12, 157-166
65. Pereira, T. N., Webb, R. I., Reilly, P. E. B., Seawright, A. A., and Prakash, A. S. (1998) Dehydromonocrotaline generates sequence-selective N-7 guanine alkylation and heat and alkali stable multiple fragment DNA crosslinks Nucl. Acid Res. 26, 5441-5447
66. Tepe, J. J. and Williams, R. M. (1999) DNA cross-linking by a phototriggered dehydromonocrotaline progenitor J. Am. Chem. Soc. 121, 2951-2955
67. Lin, G., Cui, Y. Y., and Hawes, E. M. (2000) Characterization of rat liver microsomal metabolites of clivorine, an hepatotoxic otonecine-type pyrrolizidine alkaloid Drug Metab. Dispos. 28, 1475-1483
68. Fu, P. P., Xia, Q., Lin, G., and Chou, M. W. (2004) Pyrrolizidine alkaloids-genotoxicity, metabolism enzymes, metabolic activation, and mechanisms Drug Metab. Rev. 36, 1-55
69. Fu, P. P., Xia, Q., Lin, G., and Chou, M. W. (2002) Genotoxic pyrrolizidine alkaloids-mechanism leading to DNA adduct formation and tumorigenicity Int. J. Mol. Sci. 3, 948-964
70. Yang, Y.-C., Yan, J., Doerge, D. R., Chan, P.-C., Fu, P. P., and Chou, M. W. (2001) Metabolic activation of the tumorigenic pyrrolizidine alkaloid, riddelliine, leading to DNA adduct formation in vivo Chem. Res. Toxicol. 14, 101-109
71. 32P-postlabeling/HPLC method for detection of dehydroretronecine-derived DNA adducts in vivo and in vitro Chem. Res. Toxicol. 14, 91-100
72. Xia, Q., Chou, M. W., Kadlubar, F. F., Chan, P., and Fu, P. P. (2003) Human liver microsomal metabolism and DNA adduct formation of the tumorigenic pyrrolizidine alkaloid, riddelliine Chem. Res. Toxicol. 16, 66-73
73. 1 mice Cancer Lett. 193, 119-125
74. Xia, Q., Chou, M. W., Lin, G., and Fu, P. P. (2004) Metabolic formation of DHP-derived DNA adducts from a representative otonecine type pyrrolizidine alkaloid clivorine and the extract of Ligularia hodgsonnii Hook Chem. Res. Toxicol. 17, 702-708
75. Xia, Q., Chou, M. W., Edgar, J. A., Doerge, D. R., and Fu, P. P. (2006) Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine Cancer Lett. 231, 138-145
76. Mattocks, A. R. and Bird, I. (1983) Pyrrolic and N -oxide metabolites formed from pyrrolizidine alkaloids by hepatic microsomes in vitro -relevance to in vivo hepatotoxicity Chem.-Biol. Interact. 43, 209-222
77. Bull, L. B. and Dick, A. T. (1959) The chronic pathological effects on the liver of the rat of the pyrrolizidine alkaloids heliotrine, lasiocarpine and their N -oxides J. Pathol. Bacteriol. 78, 483-502
78. Mattocks, A. R. (1971) Hepatotoxic effects due to pyrrolizidine alkaloid N -oxides Xenobiotica 1, 563-565
79. Molyneux, R. J., Johnson, A. E., Olson, J. D., and Baker, D. C. (1991) Toxicity of pyrrolizidine alkaloids from Riddell groundsel (Senecio riddellii) to cattle Am. J. Vet. Res. 52, 146-151
80. Chou, M. W., Wang, J. Y., Yang, Y.-C., Beger, R. D., Williams, L. D., Doerge, D. R., and Fu, P. P. (2003) Riddelliine N -oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine Toxicol. Lett. 145, 239-247
81. Wang, Y.-P., Yan, J., Fu, P. P., and Chou, M. W. (2005) Human liver microsomal reduction of pyrrolizidine alkaloid N -oxides to form the corresponding carcinogenic parent alkaloid Toxicol. Lett. 155, 411-420
82. Yan, J., Xia, Q., Chou, M. W., and Fu, P. P. (2008) Metabolic activation of retronecine and retronecine- N -oxide-formation of DHP-derived DNA adducts Toxicol. Ind. Health 24, 181-188
83. Cao, Y., Colegate, S. M., and Edgar, J. A. (2008) Safety assessment of food and herbal products containing hepatotoxic pyrrolizidine alkaloids: inter-laboratory consistency and the importance of N -oxide determination Phytochem. Anal. 19, 526-533
84. Mattocks, A. R. (1968) Iron (II)-catalysed conversion of unsaturated pyrrolizidine alkaloid N -oxides to pyrrole derivatives Nature 219, 480
85. Culvenor, C. C. J., Edgar, J. A., Smith, L. W., and Tweedale, H. J. (1969) Dihydropyrrolizine analogues of pyrrolizidine alkaloids Aust. J. Chem. 41, 3599-3602
86. Mattocks, A. R. (1969) Dihydropyrrolizine derivatives from unsaturated pyrrolizidine alkaloids J. Chem. Soc. C 1155-1162
87. Culvenor, C. C. J., Edgar, J. A., Smith, L. W., and Tweedale, H. J. (1970) Dihydropyrrolizines III. Preparation and reactions of derivatives related to pyrrolizidine alkaloids Aust. J. Chem. 23, 1853-1867
88. Mattocks, A. R. and Jukes, R. (1990) Trapping and measurement of short-lived alkylating agents in a recirculating flow system Chem.-Biol. Interact. 76, 19-30
89. Mattocks, A. R., Driver, H. E., Barbour, R. H., and Robins, D. J. (1986) Metabolism and toxicity of synthetic analogues of macrocyclic diester pyrrolizidine alkaloids Chem.-Biol. Interact. 58, 95-108
90. Eastman, D. F., Dimenna, G. P., and Segall, H. J. (1982) Covalent binding of two pyrrolizidine alkaloids, senecionine and seneciphylline, to hepatic macromolecules and their distribution, excretion, and transfer into milk of lactating mice Drug Metab. Dispos. 10, 236-240
91. Chou, M. W. and Fu, P. P. (2006) Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids Toxicol. Ind. Health 22, 321-327
92. Hsu, I. C., Allen, J. R., and Chesney, C. F. (1973) Identification and toxicological effects of dehydroretronecine-metabolite of monocrotaline Proc. Soc. Exp. Biol. Med. 144, 834-838
93. Hsu, I. C., Robertson, K. A., Shumaker, R. C., and Allen, J. R. (1975) Binding of tritiated dehydroretronecine to macromolecules Res. Commun. Chem. Pathol. Pharmacol. 11, 99-106
94. Curtain, C. C. and Edgar, J. A. (1976) The binding of dehydroheliotridine to DNA and the effect of it and other compounds on repair synthesis in main and satellite band DNA Chem.-Biol. Interact. 13, 243-256
95. Sun, P. S., Hsia, M-T. S., Chu, F. S., and Allen, J. R. (1977) Inhibition of yeast alcohol dehydrogenase by dehydroretronecine Food Cosmet. Toxicol. 15, 419-422
96. Seawright, A. A. (1992) Potential toxicity problems with herbal medicines and food-new observations with pyrrolizidine alkaloids Proc. Nutr. Soc. Aust. 17, 20-25
97. Seawright, A. A. (1994) Toxic plant residues in meat, in Plant-Associated Toxins; Agricultural, Phytochemical and Ecological Aspects (Colegate, S. M. and Dorling, P. R., Eds.) Chapter 15, pp 77-84, CAB International, Wallingford UK.
98. Hsu, I. C., Schumaker, R. C., and Allen, J. R. (1974) Tissue distribution of tritium-labeled dehydroretronecine Chem.-Biol. Interact. 8, 163-170
99. Hsu, I. C., Robertson, K. A., and Allen, J. R. (1976) Tissue distribution, binding properties and lesions produced by dehydroretronecine in the non-human primate Chem.-Biol. Interact. 12, 19-28
100. Shumaker, R. C., Hsu, I. C., and Allen, J. R. (1976) Localisation and tissue effects of tritiated dehydroretronecine in young rats J. Pathol. 119, 21-28
101. 3H]synthanecine a bis- N -ethylcarbamate and its metabolites in the rat Chem.-Biol. Interact. 15, 173-184
102. 3H] senecionine to DNA of rat liver, lung and kidney Chem.-Biol. Interact. 54, 57-69
103. Mattocks, A. R. and Jukes, R. (1990) Recovery of the pyrrolic nucleus of pyrrolizidine alkaloid metabolites from sulphur conjugates in tissues and body fluids Chem.-Biol. Interact. 75, 225-239
104. Allen, J. R., Hsu, I.-C., and Carstens, L. A. (1975) Dehydroretronecine induced rhabdomyosarcomas in rats Cancer Res. 35, 997-1002
105. Shumaker, R. C., Robertson, K. A., Hsu, I. C., and Allen, J. R. (1976) Neoplastic transformation in tissues of rats exposed to monocrotaline or dehydroretronecine J. Natl. Cancer Inst. 56, 787-789
106. Peterson, J. E., Jago, M. V., Reddy, J. K., and Jarrett, R. G. (1983) Neoplasia and chronic disease associated with the prolonged administration of dehydroheliotridine to rats J. Natl. Cancer Inst. 70, 381-386
107. Percy, J. and Pierce, A. E. (1971) Immunosuppressive activity of the pyrrolizidine alkaloid metabolite dehydroheliotridine Immunology 21, 273-280
108. Peterson, J. E., Samuel, A., and Jago, M. V. (1972) Pathological effects of dehydroheliotridine, a metabolite of heliotridine-based pyrrolizidine alkaloids in the young rat J. Pathol. 107, 175-189
109. Mattocks, A. R. and Bird, I. (1983) Alkylation by dehydroretronecine, a cytotoxic metabolite of some pyrrolizidine alkaloids: an in vivo test Toxicol. Lett. 16, 1-8
110. Prakash, A. S., Pereira, T. N., Reilly, P. E. B., and Seawright, A. A. (1999) Pyrrolizidine alkaloids in human diet Mutat. Res. 443, 53-67
111. Hooper, P. T. (1975) Experimental acute gastrointestinal disease caused by the pyrrolizidine alkaloid, lasiocarpine J. Comp. Pathol. 85, 341-349
112. Wong, L. S.N., Lamé, M. W., Jones, A. D., and Wilson, D. W. (2010) Differential cellular responses to protein adducts of naphthoquinone and monocrotaline pyrrole Chem. Res. Toxicol. 23, 1504-1513
113. Molyneux, R. J., Johnson, A. E., and Stuart, L. D. (1988) Delayed manifestation of Senecio -induced pyrrolizidine alkaloidosis in cattle: case reports Vet. Hum. Toxicol. 30, 201-205
114. DeLeve, L. D., Wang, X., Kuhlenkamp, J. F., and Kaplowitz, N. (1996) Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: the role of glutathione and relevance to hepatic venooclusive disease Hepatology 23, 589-599
115. DeLeve, L. D., McCuskey, R. S., Wang, X., Hu, L., McCuskey, M. K., Epstein, R. B., and Kanel, G. C. (1999) Characterization of a reproducible rat model of hepatic veno-occlusive disease Hepatology 29, 1779-1791
116. DeLeve, L. D., Shulman, H. M., and McDonald, G. B. (2002) Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) Semin. Liver Dis. 22, 27-41
117. DeLeve, L. D., Ito, Y., Bethea, N. W., McCuskey, M. K., Wang, X., and McCuskey, R. S. (2003) Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome Am. J. Physiol.: Gastrointest. Liver Physiol. 284, G1045-G1052
118. DeLeve, L. D., Valla, D.-C., and Garcia-Tsao, G. (2009) Vascular disorders of the liver Hepatology 49, 1729-1764
119. Huxtable, R. J. (1989) Human health implications of pyrrolizidine alkaloids and herbs containing them, in Toxicants of Plant Origin (Cheeke, P. R., Ed). Vol. 1, Chapter 3, pp 42-86, CRC Press, Inc., Boca Raton, FL.
120. Nolan, J. P., Scheig, R. L., and Klatskin, G. (1966) Delayed hepatitis and cirrhosis in weanling rats following a single small dose of the Senecio alkaloid, lasiocarpine Am. J. Pathol. 49, 129-151
121. Gordon, G. J., Coleman, W. B., and Grisham, J. W. (2000) Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats Am. J. Pathol. 157, 771-786
122. Hanumegowda, U. M., Copple, B. L., Shibuya, M., Malle, E., Ganey, P. E., and Roth, R. A. (2003) Basement membrane and matrix metalloproteinases in monocrotaline-induced liver injury Toxicol. Sci. 76, 237-246
123. Wang, X., Kanel, G. C., and DeLeve, L. D. (2000) Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat Hepatology 31, 428-434
124. Ridker, P. M., Ohkuma, S., McDermott, W. V., Trey, C., and Huxtable, R. J. (1985) Hepatic venooclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements Gastroenterology 88, 1050-1054
125. Rasenack, R., Müller, C., Kleinschmidt, M., Rasenack, J., and Wiedenfeld, H. (2003) Veno-occlusive disease in a fetus caused by pyrrolizidine alkaloids of food origin Fetal Diagn. Ther. 18, 223-225
126. Kay, J. M. and Heath, D. (1966) Observations on the pulmonary arteries and heart weight of rats fed on Crotalaria spectabilis seeds J. Pathol. Bacteriol. 92, 385-394
127. Heath, D. and Kay, J. M. (1967) Medial thickness of pulmonary trunk in rats with cor pulmonale induced by ingestion of Crotalaria spectabilis seeds Cardiovasc. Res. 1, 74-79
128. Kay, J. M., Harris, P., and Heath, D. (1967) Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds Thorax 22, 176-179
129. Burns, J. (1972) The heart and pulmonary arteries in rats fed on Senecio jacobaea J. Pathol. 106, 187-194
130. Allen, J. R. and Chesney, C. F. (1972) Effect of age on development of cor pulmonale in non-human primates following pyrrolizidine alkaloid intoxication Exp. Mol. Pathol. 17, 220-232
131. Chesney, C. F. and Allen, J. R. (1973) Endocardial fibrosis associated with monocrotaline induced pulmonary hypertension in non-human primates (Macaca arctoides) Am. J. Vet. Res. 34, 1577-1581
132. Chesney, C. F. and Allen, J. R. (1973) Monocrotaline induced pulmonary vascular lesions in non-human primates Cardiovasc. Res. 7, 508-518
133. Fishman, A. P. (1974) Dietary pulmonary hypertension Circ. Res. 35, 657-660
134. Pan, L. C., Wilson, D. W., Lamé, M. W., Jones, A. D., and Segall, H. J. (1993) Cor pulmonale is caused by monocrotaline and dehydromonocrotaline, but not by glutathione or cysteine conjugates of dihydropyrrolizine Toxicol. Appl. Pharmacol. 118, 87-97
135. Sehgal, P. B. and Mukhopadhyay, S. (2007) Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension Am. J. Respir. Cell Mol. Biol. 37, 31-37
136. Stenmark, K. R., Meyrick, B., Galie, N., Mooi, W. J., and McMurtry, I. F. (2009) Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure Am. J. Physiol.: Lung Cell. Mol. Physiol. 297, L1013-1032
137. Yen, C. H., Tsai, T. H., Leu, S., Chen, Y. L., Chang, L. T., Chai, H. T., Chung, S. Y., Chua, S., Tsai, C. Y., Chang, H. W., Ko, S. F., Sun, C. K., and Yip, H. K. (2013) Sildenafil improves long term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension Cytotherapy 15, 209-223
138. 1 ameliorate symptoms and progression of pulmonary hypertension at a reduced dosing frequency Mol. Pharmaceutics 10, 1655-1667
139. Gomez-Arroyo, J. G., Farkas, L., Alhussaini, A. A., Farkas, D., Kraskauskas, D., Voelkel, N. F., and Bogaard, H. J. (2012) The monocrotaline model of pulmonary hypertension in perspective Am. J. Physiol.: Lung Cell. Mol. Physiol. 302, L363-369
140. Kay, J. M., Heath, D., Smith, P., Bras, G., and Summerell, J. (1971) Fulvine and pulmonary circulation Thorax 26, 249-261
141. Heath, D., Shaba, J., Williams, A., Smith, P., and Kombe, A. (1975) A pulmonary hypertension-producing plant from Tanzania Thorax 30, 399-404
142. Györika, S. and Stricker, H. (2009) Severe pulmonary hypertension possibly due to pyrrolizidine alkaloids in polyphytotherapy Swiss Med. Wkly. 139, 210-211
143. Couet, C. E., Hanley, A. B., MacDonald, S., and Mayes, L. (1993) The biological assay of natural mutagens using p53, in Food and Cancer Prevention (Waldron, K. W., Johnston, I. T., and Fenwick, G. R., Eds.) pp 426-428, Royal Society of Chemistry, London.
144. Ji, L., Zhang, M., Sheng, Y., and Wang, Z. (2005) Pyrrolizidine alkaloid clivorine induces apoptosis in human normal liver L-20 cells and reduces the expression of p53 protein Toxicol. In Vitro 19, 41-46
145. Hirono, I. (1993) Edible plants containing naturally occurring carcinogens in Japan Jpn. J. Cancer Res. 84, 997-1006
146. Chan, P. C., Haseman, J. K., Prejean, J. D., and Nyska, A. (2003) Toxicity and carcinogenicity of riddelliine in rats and mice Toxicol. Lett. 144, 295-311
147. Malkin, D. (2011) Li-Fraumeni syndrome Genes Cancer 2, 475-484
148. LeTendre, L., Ludwig, J., Perrault, J., Smithson, W. A., and Kovach, J. S. (1984) Hepatocellular toxicity during treatment of refractory acute leukemia with indicine N -oxide Cancer 54, 1256-1259
149. Miser, J. S., Smithson, W. A., Krivit, W., Hughes, C., Davis, D., Krailo, M., and Hammond, D. (1991) Phase II trial of indicine N -oxide in relapsed pediatric solid tumors Invest. New Drugs 9, 339-342
150. Rai, P. R., Cool, C. D., King, J. A. C., Stevens, T., Burns, N., Winn, R. A., Kasper, M., and Voelkel, N. F. (2008) The cancer paradigm of severe pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 178, 558-564
151. Schoental, R. (1968) Toxicology and carcinogenic action of pyrrolizidine alkaloids Cancer Res. 28, 2237-2246
152. McLean, E. K. (1970) The toxic actions of pyrrolizidine (Senecio) alkaloids Pharmacol. Rev. 22, 429-483
153. Svoboda, D. J. and Reddy, J. K. (1972) Malignant tumors in rats given lasiocarpine Cancer Res. 32, 908-912
154. Hirono, I., Shimizu, M., Fushimi, K., Mori, H., and Kato, K. (1973) Carcinogenic activity of Petasites japonicus Maxim, a kind of coltsfoot Gann Monogr. Cancer Res. 64, 527-528
155. Hirono, I., Mori, H., and Haga, M. (1978) Carcinogenic activity of Symphytum officinale J. Natl. Cancer Inst. 61, 865-869
156. Kanwar, V. S., Albuquerque, M. L., Ribeiro, R. C., Kauffman, W. M., and Furman, W. L. (1995) Veno-occlusive disease of the liver after chemotherapy for rhabdomyosarcoma: case report with a review of the literature Med. Pediatr. Oncol. 24, 334-340
157. Ortega, J. A., Donaldson, S. S., Ivy, S. P., Pappo, A., and Maurer, H. M. (1997) Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma Cancer 79, 2435-2439
158. Bisogno, G., de Kraker, J., Weirich, A., Masiero, L., Ludwig, R., Tornade, M. F., and Carli, M. (1997) Veno-occlusive disease of the liver in children treated for Wilms tumor Med. Pediatr. Oncol. 29, 245-251
159. Ludwig, R., Weirich, A., Abel, U., Hofmann, W., Graf, N., and Tournade, M. F. (1999) Hepatotoxicity in patients treated according to the nephroblastoma trial and study SIOP-9/GPOH Med. Pediatr. Oncol. 33, 462-469
160. Burkhardt, A. and Klöppel, A. (1977) Unusual obliterative disease of the hepatic veins in an infant Virchows Arch. A: Pathol. Anat. Histol. 375, 225-232
161. Rubbia-Brandt, L., Audard, V., Sartoretti, P., Roth, A. D., Brezault, C., Le Charpentier, M., Dousset, B., Morel, P., Soubrane, O., Chausade, S., Mentha, G., and Terris, B. (2004) Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer Ann. Oncol. 15, 460-466
162. Boula, A. M., Mantadakis, E., Xilouri, I. M., Christoforidou, A. V., Foudoulakis, A. M., and Samonis, G. (2005) Veno-occlusive disease of the liver associated with chronic myelomonocytic leukemia treated with vincristine and standard doses of cytarabine Am. J. Hematol. 79, 216-219
163. Elli, M., Pinarli, F. G., Dagdemir, A., and Acar, S. (2006) Veno-occlusive disease of the liver in a child after chemotherapy for brain tumor Pediatr. Blood Cancer 46, 521-523
164. Matute-Bello, G., McDonald, G. D., Hinds, M. S., Schoch, H. G., and Crawford, S. W. (1998) Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation Bone Marrow Transplant. 21, 1152-1130
165. McDonald, G. B., Hinds, M. S., Fisher, L. D., Schoch, H. G., Wolford, J. L., Banaji, M., Hardin, B. J., Shulman, H. M., and Clift, R. A. (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients Ann. Int. Med. 118, 255-267
166. Strasser, S. I., Sullivan, K. M., Myerson, D., Spurgeon, C. L., Storer, B., Schoch, H. G., Murakami, C. S., and McDonald, G. B. (1999) Cirrhosis of the liver in long-term marrow transplant survivors Blood 93, 3259-3266
167. Copelan, E. A., Penza, S. L., Elder, P. J., Ezzone, S. A., Scholl, M. D., Bechtel, T. P., Belt, P. S., and Avalos, B. R. (2000) Analysis of prognostic factors for allogenic marrow transplantation following busulfan and cyclophosphamide in myelodysplastic syndrome and after leukemic transformation Bone Marrow Transplant. 25, 1219-1222
168. Horn, B., Reiss, U., Matthay, K., McMillan, A., and Cowan, M. (2002) Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progentitor cell transplantation: a high incidence in patients with neuroblastoma Bone Marrow Transplant. 29, 409-415
169. Bairey, O., Kirgner, I., Yakobi, M., Hamdan, A., Ben-Ari, Z., and Shaklai, M. (2002) Clinical severe hepatic venooclusive disease during induction treatment of acute monoblastic leukemia managed with defibrotide Am. J. Hematol. 69, 281-284
170. Barker, C. C., Butzner, J. D., Anderson, R. A., Brant, R., and Sauve, R. S. (2003) Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients Bone Marrow Transplant. 32, 79-87
171. Kraemer, D. M., Waschke, J., and Kunzmann, V. (2003) Venoocclusive disease in a male patient with Marfam syndrome and common acute lymphoblastic leukemia during induction therapy Ann. Hematol. 82, 444-447
172. Bajwa, R. P. S., Cant, A. J., Abinun, M., Flood, T. J., Hodges, S., Hale, J. P., and Skinner, R. (2003) Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment Bone Marrow Transplant. 31, 591-597
173. Kalayoglu-Besisik, S., Yenerel, M. N., Caliskan, Y., Ozturk, S., Besisik, F., and Sargin, D. (2005) Time-related changes in the incidence severity and clinical outcome of hepatic veno-occlusive disease in hematopoietic stem cell transplantation patients during the past ten years Transplant. Proc. 37, 2285-2289
174. Papadopoulos, A., Ntaios, G., Kaiafa, G., Girtovitis, Z. S., Kontoninas, Z., Diamantidis, M. D., Savopoulos, C., and Hatzitolios, A. (2008) Veno-occlusive disease of the liver during induction therapy for acute lymphoblastic leukemia Int. J. Hematol. 88, 441-442
175. Dulley, F. L., Kanfer, E. J., Appelbaum, F. R., Amos, D., Hill, R. S., Buckner, C. D., Shulman, H. M., McDonald, G. B., and Thomas, E. D. (1987) Veno-occlusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation Transplantation 43, 870-873
176. Carreras, E. (2000) Veno-occlusive disease of the liver after hemopoietic cell transplantation Eur. J. Haematol. 64, 281-291
177. Kumar, S., DeLeve, L. D., Kamath, P. S., and Tefferi, A. (2003) Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation Mayo Clin. Proc. 78, 589-598
178. Gharib, M. I., Bulley, S. R., Doyle, J. J., and Wynn, R. F. (2006) Venous occlusive disease in children Thromb. Res. 118, 27-38
179. Rubbia-Brandt, L., Tauzin, S., Brezault, C., Delucinge-Vivier, C., Descombes, P., Dousset, P. E., Mentha, G., and Terris, B. (2011) Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans Mol. Cancer Ther. 10, 687-696
180. De Jonge, M. E., Huitema, A. D. R., Beijnen, J. H., and Rodenhuis, S. (2006) High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy Br. J. Cancer 94, 1226-1230
181. Plapp, F. V. and Chiga, M. (1972) Disaggregation of mouse liver polysomes by cyclophosphamide Arch. Pharmacol 272, 351-353
182. Yan, C. C. and Huxtable, R. J. (1996) Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat Biochem. Pharmacol. 51, 375-379
183. Hettmer, S. and Wagers, A. J. (2010) Uncovering the origins of rhabdomyosarcoma Nat. Med. 16, 171-173
184. Daughton, C. G. (2005) Overlooked in Fallon? Environ. Health Perspect. 113, A224
185. Morty, R. E., Nejman, B., Kwapiszewska, G., Hecker, M., Zakrzewicz, A., Kouri, F. M., Peters, D. M., Dumitrascu, R., Seeger, W., Knaus, P., Schermuly, R. T., and Eickelberg, O. (2007) Dysregulated bone morphogenetic Protein signaling in monocrotaline-induced pulmonary arterial hypertension Arterioscler., Thromb., Vasc. Biol. 27, 1072-1078
186. Murakami, K., Mathew, R., Huang, J., Farahani, R., Peng, H., Olson, S. C., and Etlinger, J. D. (2010) Smurf1 ubiquitin ligase causes downregulation of BMP receptors and is induced in monocrotaline and hypoxia models of pulmonary arterial hypertension Exp. Biol. Med. 235, 805-813
187. Ramos, M., Lamé, M. W., Segall, H. J., and Wilson, D. W. (2007) Monocrotaline pyrrole induces Smad nuclear accumulation and altered signaling expression in human pulmonary arterial endothelial cells Vasc. Pharmacol. 46, 439-448
188. Owens, G. K., Rabinovitch, P. S., and Schwartz, S. M. (1981) Smooth muscle hypertrophy versus hyperplasia in hypertension Proc. Natl. Acad. Sci. U.S.A. 78, 7759-7763
189. Veyssier-Belot, C. and Cacoub, P. (1999) Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension Cardiovasc. Res. 44, 274-282
190. Tajsic, T. and Morrell, N. W. (2011) Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension Comp. Physiol. 1, 295-317
191. Lappin, P. B. and Roth, R. A. (1997) Hypertrophy and prolonged DNA synthesis in smooth muscle cells characterize pulmonary arterial wall thickening after monocrotaline pyrrole administration Toxicol. Pathol. 25, 372-380
192. Lappin, P. B., Ross, K. L., King, L. E., Fraker, P. J., and Roth, R. A. (1998) The response of pulmonary vascular endothelial cells to monocrotaline pyrrole: cell proliferation and DNA synthesis in vitro and in vivo Toxicol. Appl. Pharmacol. 150, 37-48
193. Lee, J., Reich, R., Xu, F., and Sehgal, P. B. (2009) Golgi, trafficking, and mitosis dysfunction in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging Am. J. Physiol.: Lung Cell. Mol. Physiol. 297, L715-L728
194. Mukhopadhyay, S., Shah, M., Xu, F., Patel, K., Tuder, R. M., and Sehgal, P. B. (2008) Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension Am. J. Physiol.: Lung Cell Mol. Physiol. 249, L449-L468
195. Bull, L. B. (1955) The histological evidence of liver damage from pyrrolizidine alkaloids: megalocytosis of the liver cells and inclusion globules Aust. Vet. J. 31, 33-40
196. Jago, M. V. (1969) The development of the hepatic megalocytosis of chronic pyrrolizidine alkaloid poisoning Am. J. Pathol. 56, 405-422
197. Svoboda, D., Reddy, J., and Bunyaratvej, S. (1971) Hepatic megalocytosis in chronic lasiocarpine poisoning Am. J. Pathol. 65, 399-408
198. Samuel, A. and Jago, M. V. (1975) Localization in the cell cycle of the antimitotic action of the pyrrolizidine alkaloid lasiocarpine and of its metabolite, dehydroheliotridine Chem.-Biol. Interact. 10, 185-197
199. Runo, J. R. and Loyd, J. E. (2003) Primary pulmonary hypertension Lancet 361, 1533-1544
200. Aldred, M. A., Comhair, S. A., Varella-Garcia, M., Asosingh, K., Xu, W., Noon, G. P., Thistlewaite, P. A., Tuder, R. M., Erzurum, S. C., Geraci, M. W., and Coldren, C. D. (2010) Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 182, 1153-1160
201. Austin, E. D., Hamid, R., and Ahmed, F. (2010) Somatic mutations in pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 182, 1095-1095
202. Taura, P., Garcia-Valdecasas, J. C., Beltran, J., Izquierdo, E., Navasa, M., Sala-Blanch, J., Mas, A., Balust, J., Grande, L., and Visa, J. (1996) Moderate primary pulmonary hypertension in patients undergoing liver transplantation Anesth. Analg. 83, 675-680
203. Hoeper, M. M., Krowka, M. J., and Strassburg, C. P. (2004) Portopulmonary hypertension and hepatopulmonary syndrome Lancet 363, 1461-1468
204. Herve, P., Le Pavec, J., Sztrymf, B., Decante, B., Savale, L., and Sitbon, O. (2007) Pulmonary vascular abnormalities in cirrhosis Best Pract. Res., Clin. Gastroenterol. 21, 141-159
205. Kochar, R., Moises, I., Rubin, N., and Fallon, M. B. (2011) Pulmonary complications of cirrhosis Curr. Gastroenterol. Rep. 13, 34-39
206. McDonnell, P. J., Toye, P. A., and Hutchins, G. M. (1983) Primary pulmonary hypertension and cirrhosis: are they related? Am. Rev. Respir. Dis. 127, 437-441
207. Murata, K., Shimizo, A., Takase, K., Nakano, T., and Tameda, Y. (1997) Asymptomatic primary pulmonary hypertension associated with liver cirrhosis J. Gastroenterol. 32, 102-104
208. Bragdon, B., Moseychuk, O., Saldanha, S., King, D., Julian, J., and Nohe, A. (2011) Bone morphogenetic proteins: a critical review Cell. Signalling 23, 609-620
209. Okamoto, M., Murai, J., Yoshikawa, H., and Tsumali, N. (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development J. Bone Miner. Res. 21, 1022-1033
210. Steward, C. G., Pellier, I., Mahajan, A., Ashworth, M. T., Stuart, A. G., Fasth, A., Lang, D., Fischer, A., Friedrich, W., and Schulz, A. S. (2004) Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis Br. J. Hamaetol. 124, 63-71
211. Slatter, M. A., Rao, K., Amrolia, P., Flood, T., Abinun, M., Hambleton, S., Nademi, Z., Goulden, N., Davies, G., Qasim, W., Gaspar, H. B., Cant, A., Gennery, A. R., and Veys, P. (2011) Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency (PID): UK experience Blood 117, 4367-4375
212. Kaplan, F. S., Zasloff, M. A., Kitterman, J. A., Shore, E. M., Hong, C. X., and Rocke, D. M. (2010) Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva J. Bone Jt. Surg., Am. Vol. 92, 686-691
213. Xu, M.-Q., Feldman, G., LeMerrer, M., Shugart, Y. Y., Glaser, D. L., Urtizberea, J. A., Fardeau, M., Connor, J. M., Triffitt, J., Smith, R., Shore, E. M., and Kaplan, F. S. (2000) Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressive (FOP) Clin. Genet. 58, 291-298
214. Gannon, F. H., Kaplan, F. S., Olmsted, E., Finkel, G. C., Zasloff, M. A., and Shore, E. S. (1997) Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressive Human Pathol. 28, 339-343
215. Enklaar, T., Zabel, B. U., and Prawitt, D. (2006) Beckwith-Wiedemann syndrome: multiple molecular mechanisms Expert Rev. Mol. Med. 8, 1-19
216. Sun, J., Liu, Y.-H., Chen, H., Nguyen, M. P., Mishina, Y., Upperman, J. S., Ford, H. R., and Shi, W. (2007) Deficient Alk3-mediated BMP signaling causes prenatal omphalocele-like defect Biochem. Biophys. Res. Commun. 360, 238-243
217. Sotelo-Avila, C. and Gooch, W. M. (1976) Neoplasms associated with the Beckwith-Weidemann syndrome Perspect. Pediatr. Pathol. 3, 255-272
218. Rump, P., Zeegers, M. P. A., and van Essen, A. J. (2005) Tumor risk in Beckwith-Wiedemann syndrome: a review and meta-analysis Am. J. Med. Gen. 136A, 95-104
219. Spector, L. G. and Birch, J. (2012) The epidemiology of hepatoblastoma Pediatr. Blood Cancer 59, 776-779
220. Bardeesy, N., Falkoff, D., Petruzzi, M., Nowak, N., Zabel, B., Adam, M., Agiar, M. C., Grundy, P., Shows, T., and Pelletier, J. (1994) Anaplastic Wilm's tumour, a subtype displaying poor prognosis, harbours p53 gene mutations Nat. Genet. 7, 91-97
221. Muwakkit, S., Antillon, F., Valverde, P., Jenkins, J. J., Zaatari, G., and Dome, J. S. (2002) Letter to the Editor: Simultaneous occurrence of Wilms tumor and rhabdomyosarcoma in two patients Med. Pediatr. Oncol. 39, 143-145
222. Müller-Höcker, J., Weiss, M., Meyer, U., Schramel, P., Wiebecke, B., Belohradsky, B. H., and Hübner, G. (1987) Fatal copper storage disease of the liver in a German infant resembling Indian childhood cirrhosis Virchows Arch. A: Pathol. Anat. Histopathol. 411, 379-385
223. Price, L. A., Walker, N. I., Clague, A. E., Pullen, I. D., Smits, S. J., Ong, T.-H., and Patrick, M. (1996) Chronic copper toxicosis presenting as liver failure in an Australian child Pathology 28, 316-320
224. Seibold-Weiger, K., Vochem, M., Mackensen-Haen, S., and Speer, C. (1997) Fatal hepatic veno-occlusive disease in a newborn infant Am. J. Perinatol. 14, 107-111
225. Sergi, C., Beedgen, B., Linderkamp, O., and Hofmann, W. J. (1999) Fatal course of veno-occlusive disease of the liver (Endophlebitis Hepatica obliterans) in a preterm infant Pathol., Res. Pract. 195, 847-851
226. Trollmann, R., Neureiter, D., Lang, T., Dörr, H. G., and Behrens, R. (1999) Late manifestation of Indian childhood cirrhosis in a 3-year-old German girl Eur. J. Pediatr. 158, 375-378
227. Bull, L. B., Dick, A. T., Keast, J. C., and Edgar, G. (1956) An experimental investigation of the hepatotoxic and other effects on sheep of consumption of Heliotropium europaeum L.: heliotrope poisoning of sheep Aust. J. Agric. Res. 7, 281-331
228. St George-Grambauer, T. D. and Rac, R. (1962) Hepatogenous chronic copper poisoning in sheep in South Australia due to the consumption of Echium plantagineum L. (Salvation Jane) Aust. Vet. J. 38, 288-293
229. Miranda, C. L., Henderson, M. C., and Buhler, D. R. (1981) Dietary copper enhances the hepatotoxicity of Senecio jacobaea in rats Toxicol. Appl. Pharmacol. 60, 418-423
230. Howell, J. M., Deol, H. S., Dorling, P. R., and Thomas, J. B. (1991) Experimental copper and heliotrope intoxication in sheep: morphological changes J. Comp. Pathol. 105, 49-74
231. Walker-Smith, J. and Blomfield, J. (1973) Wilson's disease or chronic copper poisoning? Arch. Dis. Child. 48, 476-479
232. Müller-Höcker, J., Meyer, U., Wiebecke, B., Hübner, G., Eife, R., Kellner, M., and Schramel, P. (1988) Copper storage disease of the liver and chronic dietary copper intoxication in two further German infants mimicking Indian Childhood Cirrhosis Pathol., Res. Pract. 183, 39-45
233. Müller-Höcker, J., Summer, K. H., Schramel, P., and Rodeck, B. (1998) Different pathomorphic patterns in exogenic infantile copper intoxication of the liver Pathol., Res. Pract. 194, 377-384
234. Von Mühlendahl, K. E. and Lange, H. (1994) Copper and childhood cirrhosis Lancet 344, 1515-1516
235. Scheinberg, I. H. and Sternlieb, I. (1994) Is non-Indian childhood cirrhosis caused by excess dietary copper? Lancet 344, 1002-1004
236. Baker, A., Gormally, S., Saxena, R., Baldwin, D., Drumm, B., Bonham, J., Potmann, B., and Mowat, A. P. (1995) Copper-associated liver disease in childhood J. Hepatol. 23, 538-543
237. Müller, T., Feichtinger, H., Berger, H., and Müller, W. (1996) Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder Lancet 347, 877-880
238. Müller, T., Müller, W., and Feichtinger, H. (1998) Idiopathic copper toxicosis Am. J. Clin. Nutr. 67, 1082S-1986S
239. Wijmenga, C., Müller, T., Brunt, T., Feichtinger, H., Schönitzer, D., Houwen, R. H. J., Müller, W., Sandkuijl, L. A., and Pearson, P. L. (1998) Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease Eur. J. Hum. Genet. 6, 624-628
240. Tanner, M. S. (1998) Role of copper in Indian childhood cirrhosis Am. J. Clin. Nutr. 67, 1074S-1081S
241. Aston, N. S., Morris, P. A., Tanner, M. S., and Variend, S. (1998) An animal model for copper-associated cirrhosis in infancy J. Pathol. 186, 215-221
242. Dieter, H. H., Schimmelpfennig, W., Meyer, E., and Tabert, M. (1999) Early childhood cirrhosis (ECC) in Germany between 1982 and 1994 with special consideration of copper etiology Eur. J. Med. Res. 28, 233-242
243. Zietz, B. P., de Vergara, J. D., and Dunkelberg, H. (2003) Copper concentrations in tap water and possible effects on infant's health-results of a study in Lower Saxony, Germany Environ. Res. 92, 129-138
244. Zietz, B. P., Dieter, H. H., Lakomek, M., Schneider, H., Kessler-Gaedke, B., and Dunkelberg, H. (2003) Epidemiological investigation on chronic copper toxicity to children exposed via the public drinking water supply Sci. Total Environ. 302, 127-144
245. Mellis, C. and Bales, P. M. (1976) Familial hepatic venoocclusive disease with probable immune deficiency J. Pediatr. 88, 236-242
246. Etzioni, A., Benderly, A., Rosenthal, E., Shehadah, V., Auslander, L., Lahat, N., and Pollack, S. (1987) Defective humoral and cellular immune functions associated with veno-occlusive disease of the liver J. Pediatr. 110, 549-554
247. Roscioli, T., Cliffe, S. T., Bloch, D. B., Bell, C. G., Mullan, G., Taylor, P. J., Sarris, M., Wang, J., Donald, J. A., Kirk, E. P., Ziegler, J. B., Salzer, U., McDonald, G. B., Wong, M., Lindeman, R., and Buckley, M. F. (2006) Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease Nat. Genet. 38, 620-622
248. Cliffe, S. T., Wong, M., Taylor, P. J., Ruga, E., Wilcken, B., Lindeman, R., Buckley, M. F., and Roscioli, T. (2007) The first prenatal diagnosis for veno-occlusive disease and immunodeficiency syndrome, an autosomal recessive condition associated with mutation in SP110 Prenatal Diagn. 27, 674-676
249. Cliffe, S. T., Bloch, D. B., Suryani, S., Kamsteeg, E.-J., Avery, D. T., Palendira, U., Church, J. A., Wainstein, B. K., Trizzino, A., Lefranc, G., Akatcherian, C., Megarbane, A., Gilissen, C., Moshous, D., Reichenbach, J., Ziegler, J. B., Wong, M., Tangye, S. G., Lindeman, R., Buckley, M. F., and Roscioli, T. (2012) Clinical, molecular, and cellular immunological findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome J. Allergy Clin. Immunol. 130, 735-742
250. Wang, T., Ong, P., Roscioli, T., Cliffe, S. T., and Church, J. A. (2012) Hepatic veno-occlusive disease with immunodeficiency (VODI): first reported case in the U.S. and identification of a unique mutation in Sp110 Clin. Immunol. 145, 102-107
251. Ganaiem, H., Eisenstein, E. M., Tenenbaum, A., Somech, R., Simanovsky, N., Roscioli, T., Weintraub, M., and Stepensky, P. (2013) The role of hematopoietic stem cell transplantation in SP110 associated veno-occlusive disease with immunodeficiency syndrome Pediatr. Allergy Immunol. 24, 250-256
252. (2009) Genetics Home Reference, US National Library of Medicine, http://ghr.nlm.nih.gov/gene/SP110.
253. Deyo, J. A. and Kerkvliet, N. I. (1990) Immunotoxicity of the pyrrolizidine alkaloid monocrotaline following subchronic administration to C57B1/6 mice Fundam. Appl. Toxicol. 14, 842-849
254. Molyneux, R. J., Gardner, D. L., Colegate, S. M., and Edgar, J. A. (2011) Pyrrolizidine alkaloid toxicity in livestock: a paradigm for human poisoning? Food Addit. Contam., Part A 28, 293-307
255. 1 in liver carcinogenesis Plant Foods Man 1, 23-31
256. Yee, S. B., Kinser, S., Hill, D. A., Barton, C. C., Hotchkis, J. A., Harkema, J. R., Ganey, P. E., and Roth, R. A. (2000) Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline Toxicol. Appl. Pharmacol. 166, 173-185
257. (1992) Abwehr von Arzneimittelrisiken-Stufe II. Bundesanzeiger 17 June, 4805; cited by Dtsch. Apoth. Ztg. 132, 1406-1408.
258. European Medicines Agency (2013) Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs), EMA/HMPC/893108/2011, 2nd draft, 6 Nov, EMA, London, http://www.ema.europa.eu/docs/en-GB/document-library/Public
259. Czauderna, P., Katski, K., Kowalczyk, J., Kurylak, A., Lopatka, B., Skotnicka-Klonowicz, G., Sawicz-Birkoska, K., and Godzinski, J. (2000) Venoocclusive liver disease (VOD) as a complication of Wilms' tumour management in the series of consecutive 206 patients Eur. J. Pediatr. Surg. 10, 300-303
260. Cecen, E., Uysal, K. M., Ozguven, A., and Gunes, D. (2007) Veno-occlusive disease in a child with rhabdomyosarcoma after conventional chemotherapy Pediatr. Hematol. Oncol. 24, 615-621
261. Xia, Q., Zhao, Y., Von Tungeln, L. S., Doerge, D. R., Lin, G., Cai, L., and Fu, P. P. (2013) Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity Chem. Res. Toxicol. 26, 1384-1396
262. Gao, H., Li, N., Wang, J. Y., Zhang, S. C., and Lin, G. (2012) Definitive diagnosis of hepatic obstruction syndrome induced by pyrrolizidine alkaloids J. Dig. Dis. 13, 33-39