Pyrrolizidinalkaloide und die Seneciose bei Tieren

Zusammenfassung

Pyrrolizidinalkaloide sind Pflanzentoxine, die in mehr als 6000 Pflanzenarten vorkommen. Die Seneciose der landwirtschaftlichen Nutztiere stellt eine Vergiftung mit Pyrrolizidinalkaloiden von Pflanzen der Gattung Senecio dar. Sie ist seit Ende des 19. Jahrhunderts in Deutschland, den USA, Kanada und Neuseeland bekannt und wird vor allem durch Senecio jacobaea und verwandte Senecio spp. bei landwirtschaftlichen Nutztieren einschließlich Geflügel hervorgerufen. Tiervergiftungen mit Pyrrolizidinalkaloiden spielen weltweit eine große Rolle. In unseren Breiten findet vor allem die Vergiftung von Pferden und Rindern durch das Jakobskreuzkraut (Senecio jacobaea), die als Schweinsberger Krankheit bekannt wurde, erneut besondere Beachtung in der Tiermedizin. Sie tritt fast immer als chronische Vergiftung auf und endet in der Regel tödlich. Endgültige Ursache ist die Bildung von toxischen Metaboliten der Pyrrolizidinalkaloide in der Leber, die mit Nukleinsäuren und Proteinen kovalente Bindungen eingehen und zur Leberzirrhose führen. Da viele Pyrrolizidinalkaloide mutagene und einige auch kanzerogene Wirkungen besitzen, beschäftigen sich europäische und internationale Aufsichtsbehörden mit der Frage nach möglichen Rückständen in Lebensmitteln tierischen Ursprungs. Die Übersichtsarbeit befasst sich in Teil 1 mit Aspekten des Vorkommens, der Chemie und der Toxikologie von Pyrrolizidinalkaloiden sowie mit den durch sie hervorgerufenen Pflanzenvergiftungen bei landwirtschaftlichen Nutztieren. Im zweiten Teil der Übersicht (46) erfolgt eine Darstellung des klinischen Verlaufs der Seneciose bei Tieren, von Behandlungsmaßnahmen, der erheblichen Speziesunterschiede sowie eine kritische Bewertung so genannter ungiftiger Aufnahmemengen von Senecio-Pflanzen im Tierfutter auf der Grundlage kumulativer letaler Toxindosen.

Summary

Pyrrolizidine alkaloids belong to a class of phytotoxins which are present in more than 6000 plant species. The disease seneciosis in farm animals represents the severe poisoning by pyrrolizidine alkaloids from plants of the genus Senecio. This form of poisoning has been known since the end of the 19th century in Germany, the USA, Canada and New Zealand, and is mainly caused by Senecio jacobaea and related Senecio spp. in farm animals, including poultry. Animal poisoning by pyrrolizidine alkaloids is of worldwide importance. In Germany poisoning of horses and cattle by Senecio jacobaea, which was earlier named Schweinsberg disease, is of renewed relevance for veterinary medicine. The disease occurs almost entirely as a consequence of chronic poisoning and in general ends fatally. The ultimate cause is the formation of toxic metabolites of pyrrolizidine alkaloids in the liver, and their covalent binding to nucleic acids and proteins leading to liver cirrhosis. Because many pyrrolizidine alkaloids possess mutagenic, and a few also carcinogenic properties, European and international authorities are concerned about possible residue levels in food of animal origin. The review addresses in its first part several aspects, being the occurrence, the chemistry, and the toxicology of pyrrolizidine alkaloids as well as animal intoxications by poisonous plants. In the second part (46) clinical characteristics of animal seneciosis, the therapeutic interventions, the significant species differences and a critical assessment of so-called nontoxic amounts of Senecio plants in animal fodder with reference to cumulative lethal toxin doses are presented.

Schlüsselwörter

Schweinsberger Krankheit - Pflanzengifte - Pyrrolmetabolismus - DNA-Addukte - Hepatotoxizität

Key words

Schweinsberg disease - phytotoxins - pyrrole metabolism - DNA adducts - hepatotoxicity

• Literatur

• 1 ANZFA (Australia New Zealand Food Authority). 2001 Pyrrolizidine alkaloids in food. A toxicological review and risk assessment. http://www.anzfa.gov.au
• 2 Bandyopadhyay S, Ganguly S, Mandal G, Sen R, Saha P, Ghosh MK, Sarkar M, Chatterjee M. Cytotoxicity of senecio in macrophages is mediated via its induction of oxidative stress. Res Vet Sci 2009; 87: 85-90.
• 3 Behninger C, Abel G, Röder E, Neuberger V, Göggelmann W. Wirkung eines Alkaloidextraktes von Symphytum officinale auf menschliche Lymphocytenkulturen. Planta Med 1989; 55: 518-522.
• 4 BfR (Bundesinstitut für Risikobewertung). Salatmischung mit Pyrrolizidinalkaloid-haltigem Greiskraut verunreinigt. Stellungnahme. Nr. 028/2007 vom 10. Januar 2007 http://www.bfr.bund.de/cm/208/salatmischung_mit_pyrrolizidinalkaloid_haltigem_geiskraut_verunreinigt.pdf
• 5 Brambilla G, Mattioli F, Robbiano L, Martelli A. Genotoxicity and carcinogenicity testing of pharmaceuticals: correlation between induction of DNA lesions and carcinogenic activity. Mutat Res 2010; 705: 20-39.
• 6 Bull LB, Culvenor CC, Dick AJ. The pyrrolizidine alkaloids. Their chemistry, pathogenesis and other biological properties. North-Holland, Amsterdam: 1968
• 7 Campbell JG. An investigation of the hepatotoxic effects in the fowl of Ragwort, with special reference to the induction of liver tumors with seneciphylline. Proc Roy Soc Edinburgh Sect B Biol 1956; 66: 111-130.
• 8 Chan PC, Mahler J, Buchner JR, Travlos GS, Reid JB. Toxicity and carcinogenicity of riddelliine following 13 weeks of treatment to rats and mice. Toxicon 1994; 32: 891-908.
• 9 Cheeke PR. Toxicity and metabolism of pyrrolizidine alkaloids. J Anim Sci 1988; 66: 2343-2350.
• 10 Chen T, Mei N, Fu PP. Genotoxicity of pyrrolizidine alkaloids. J Appl Toxicol 2010; 30: 183-196.
• 11 Clayson DB. Diet, mutation and cancer. Mutat Res 1985; 154: 205-217.
• 12 Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. COT statement on pyrrolizidine alkaloids in food. Food Standard Agency. 2008
• 13 Cook JW, Duffy E, Schoental R. Primary liver tumours following feeding with alkaloids of Senecio jacobaea Lin. Brit J Cancer 1950; 4: 405-410.
• 14 Cooper RA, Huxtable RJ. A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids. Toxicon 1996; 34: 604-607.
• 15 Couet CE, Hopley J, Hanley AB. Metabolic activation of pyrrolizidine alkaloids by human, rat and avocado microsomes. Toxicon 1996; 9: 1058-1061.
• 16 Coulombe RA, Drew GL, Stermitz FR. Pyrrolizidine alkaloids cross-link DNA with actin. Toxicol Appl Pharmacol 1999; 154: 198-202.
• 17 Craig JF, Kehoe D. Cirrhosis of the liver in the horse. J Comparat Pathol 1921; 35-47.
• 18 Craig JF, Kearnev W, Timoney JF. Ragwort poisoning in cattle and cirrhosis of the liver in horses. Vet Rec 1930; 10: 159-174.
• 19 EFSA. Opinion of the Scientific Panel on Contaminants in the food chain on a request from the European Commission related to pyrrolizidine alkaloids as undesirable substances in animal feed. EFSA J 2007; 447: 1-51.
• 20 Frei HJ, Luethy J, Brauchli J, Zweifel U, Wuergler FE, Schlatter C. Structure activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster. Chem-Biol Interact 1992; 83: 1-22.
• 21 Fu PP, Chou MW, Churchwell M, Wang Y, Zao Y, Xia Q, da Costa GG, Marques MM, Beland FA, Doerge DR. High-performance liquid chromatography electrospray ionization tandem mass spectrometry for the detection and quantification of pyrrolizidine alkaloid-derived DNA adducts in vitroand in vivo . Chem Res Toxicol 2010; 23: 637-652.
• 22 Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine alkaloids – Genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev 2004; 36: 1-55.
• 23 Fu PP, Chou MW, Xia Q, Yang YC, Yan J, Doerge DR, Chan PC. Genotoxic pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides – mechanism leading to DNA adduct formation and tumorigenicity. Environ Carcinogen Ecotoxicol 2001; 19: 353-386.
• 24 Furmanova M, Guzewska J, Betdowska B. Mutagenic effects of aqueous extracts of Symphytum autumnale L. and its alkaloidal fractions. J Appl Toxicol 1983; 3: 127-130.
• 25 Gilruth J. Hepatic cirrhosis of horses and cattle (Winton disease). A report on its nature, cause, and distribution. 11th Ann Rep Dep Agric. New Zealand: 1902–1903.
• 26 Gilruth J. Hepatic cirrhosis due to ragwort. Report 1904. Division of Veterinary Science. Department of Agriculture; New Zealand:
• 27 Harris PN, Chen KK. Development of hepatic tumors in rats following ingestion of Senecio longilobus. Canc Res 1970; 30: 2881-2886.
• 28 Hartmann T. Senecio: Biochemistry of the formation of pyrrolizidine alkaloids in root cultures. Biotech Agric Forest 1994; 26: 98-107.
• 29 He Y-Q, Yang L, Liu H-X, Zhang J-W, L Y Fong A, Xiong A-Z, Lu Y-L, Yang L, Wang C-H, Wang Z-T. Glucuronidation, a new metabolic pathway for pyrrolizidine alkaloids. Chem Res Toxicol 2010; 23: 591-599.
• 30 Hirono I, Haga M, Fujii M, Matsuura S, Matsubara N, Nakayama M, Furuya T, Hikichi M, Takanashi H, Uchida E, Hosaka S, Ueno I. Induction of hepatic tumors in rats by sekirkine and symphytine. J Natl Cancer Inst 1979; 63: 469-472.
• 31 Hupka E. Ist die Verfütterung von Senecio (Kreuzkraut) als Ursache der Leberverhärtung des Pferdes anzusehen?. Dtsch Tierärztl Wschr 1955; 62: 1-3.
• 32 Huxtable RJ. Herbal teas and toxins: novel aspects of pyrrolizidine poisoning in the United States. Perspect Biol Med 1980; 24: 1-14.
• 33 IARC, International Agency for Research on Cancer. Some Naturally Occuring Substances. Pyrrolizidine Alkaloids. In: Monographs on the Evaluation of Carcinogenic Risk to Humans 1976; 10: 265-353.
• 34 IARC, International Agency for Research on Cancer. Some Traditional Herbal Medicines, some Mycotoxins, Naphthalene and Styrene. Section D: Senecio Species and Riddelliine. In: Monographs on the Evaluation of Carcinogenic Risks to Humans 2002; 82: 153-168.
• 35 Joosten L, van Veen JA. Defensive properties of pyrrolizidine alkaloids against microorganisms. Phytochem Rev 2011; 10: 127-136.
• 36 Kovach JS, Ames MM, Powis G, Moertel CG, Hahn RG, Creagan ET. Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine-N-oxide, in humans. Cancer Res 1979; 39: 4540-4544.
• 37 Lanigan GW. Metabolism of pyrrolizidine alkaloids in the ovine rumen. Aust J Agric Res 1970; 21: 633-639.
• 38 Lanigan GW. Peptococcus heliotrinreducans, sp. nov., a cytochrome-producing anaerobe which metabolizes pyrrolizidine alkaloids. J Gen Microbiol 1976; 94: 1.
• 39 Levin DA. The chemical defenses of plants to pathogens and herbivores. Ann Rev Ecol System 1976; 7: 121-159.
• 40 Mattocks AR. Hepatotoxic effects due to pyrrolizidine alkaloid N-oxides. Xenobiotica 1971; 1: 563-565.
• 41 Mattocks AR. Chemistry and Toxicology of Pyrrolizidine Alkaloids. London, New York, Sydney: Academic Press; 1986
• 42 Mei N, Guo L, Fu PP, Fuscoe JC, Luan Y, Chen T. Metabolism, genotoxicity, and carcinogenicity of comfrey. J Toxicol Environ Health B Crit Rev 2010; 7–8: 509-526.
• 43 Nestmann ER, Bryant DW, Carr CJ, Fennell TT, Gallagher JE, Gorelick NJ, Swenberg JA, Williams GM. Toxicological significance of DNA adducts: summary of discussion with an expert panel. Regul Toxicol Pharmacol 1996; 24: 9-18.
• 44 NN. Meyers Großes Konversationslexikon. Leipzig 1909; 18: 180.
• 45 NTP, National Toxicology Program. Final report on carcinogens background document for riddelliine. Rep Carcinog Backgr Doc 2008; 8–5977: i-104.
• 46 Petzinger E. Pyrrolizidinalkaloide und die Seneciose bei Tieren. Teil 2: Klinik, Speziesunterschiede, Rückstandsverhalten, Grenzwerte. Tierärztl Prax (zur Publikation angenommen);
• 47 Prakash AS, Pereira TN, Reilly PE, Seawright AA. Pyrrolizidine alkaloids in human diet. Mut Res 1999; 15: 53-67.
• 48 Rizk AFM. Naturally occurring pyrrolizidine alkaloids. Boca Raton, Ann Arbor. Boston: CRC Press; 1991
• 49 Roeder E. Analysis of pyrrolizidine alkaloids. Curr Org Chem 1999; 3: 557-576.
• 50 Roeder E. Medicinal plants in Europe containing pyrrolizidine alkaloids. Pharmazie 1995; 50: 83-98.
• 51 Roulet M, Laurini R, Rivier L, Calamé A. Hepatic veno-occlusive disease in newborne infant of a woman drinking herbal tea. J Pediatr 1988; 112: 433-436.
• 52 Schoch TK, Gardner DR, Stegelmeier BI. GC/MS/MS detection of pyrrolic metabolites in animals poisoned with the pyrrolizidine alkaloid riddelliine. J Nat Toxins 2000; 9: 197-206.
• 53 Schoental R, Head MA. Senecio alkaloids. Primary liver tumours in rats. Brit J Canc 1954; 8: 458-465.
• 54 Schulz LC. Stoffwechselstörungen (Hepatosen). In: Pathologie der Haustiere, Teil II, Krankheiten und Syndrome. Schulz LC. Hrsg. Jena: Fischer; 1991: 96-98.
• 55 Siegrist-Maag S, Lüscher A, Suter M. Reaktion von Jakobskreuzkraut auf Schnitt. AGRAR-Forschung 2008; 15: 338-343.
• 56 Smith LW, Culvenor CCJ. Plant sources of hepatotoxic pyrrolizidine alkaloids. J Natural Product 1981; 44: 129-152.
• 57 Sperl W, Stuppner H, Gassner I, Judmaier W, Dietze O, Vogel W. Reversible hepatic veno-occlusive disease in an infant after consumption of a pyrrolizidine-containing herbal tea. J Pediatr 1995; 154: 112-116.
• 58 Stegelmeier BL, Edgar JA, Steven M, Gardner DR, Schoch TK, Coulumbe RA, Molyneux RJ. Pyrrolizidine alkaloid plants, metabolism and toxicity. J Natural Tox 1999; 8: 95-116.
• 59 Steenkamp V, Stewart MJ, Zuckerman M. Clinical and analytical aspects of pyrrolizidine poisoning caused by South African traditional medicines. Ther Drug Monit 2000; 22: 302-306.
• 60 Thoden TC, Boppré M, Hallmann J. Effects of pyrrolizidine alkaloids on the performance of plant-parasitic and free-living nematodes. Pest Manag Sci 2009; 65: 823-830.
• 61 Vanek J. Vergiftung mit Kreuzkraut (Senecio) als Ursache der Zdarer Pferdeseuche. Schweiz Zbl Path Bakt 1958; 21: 821-848.
• 62 Wang YP, Yan P, Fu PP, Chou MW. Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid. Toxicol Lett 2005; 155: 411-420.
• 63 Warren FL. Chapter 4: Senecio Alkaloids. In: The Alkaloids. Vol. 12; Chemistry and Physiology. Manske RHF. ed. New York, London: Academic Press; 1970: 245-331.
• 64 White RD, Krumperman PH, Cheeke PR, Deinzer ML, Buhler DR. Mutagenic responses of tansy ragwort (Senecio jacobaea) plant, pyrrolizidine alkaloids and metabolites in goat milk with salmonella/mammalian-microsome mutagenicity test. J Animal Sci 1984; 58: 1245-1254.
• 65 Wiedenfeld H, Roeder E, Bourauel T, Edgar J. eds. Pyrrolizidine Alkaloids. Structure and Toxicity. Bonn: University Press; 2008: 1-143.
• 66 Wiedenfeld H, Edgar J. Toxicity of pyrrolizidine alkaloids to humans and ruminants. Phytochem Rev 2011; 10: 137-151.
• 67 WHO. 1988. Pyrrolizidine alkaloids, Environmental Health Criteria No. 80. Geneva: International Programme on Safety; 275-337.
• 68 Williams L, Chou MW, Yan J, Young JF, Chan PC, Doerge DR. Toxicokinetics of riddelliine, a carcinogenic pyrrolizidine alkaloid, and metabolism in rats and mice. Toxicol Appl Pharmacol 2002; 182: 98-104.
• 69 www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.html
• 70 Xia Q, Chou MW, Kadlubar FF, Chan P-C, Fu PP. Human liver microsomal metabolism and DNA adduct formation of the tumorigenic pyrrolizidine alkaloid riddelliine. Chem Res Toxicol 2003; 16: 66-73.
• 71 Yan CC, Huxtable RJ. Relationship between the glutathione concentration and metabolism of the pyrrolizidine alkaloid monocrotaline in isolated perfused liver. Toxicol Appl Pharmacol 1995; 130: 13-17.
• 72 Yan J, Xia Q, Chou MW, Fu PP. Metabolic activation of retronecine and retronecine N-oxide – formation of DHP-derived DNA adducts. Toxicol Industr Health 2008; 24: 181-188.
• 73 Yang YC, Yan J, Doerge DR, Daniel R, Chan PC, Fu PP, Chou MW. Metabolic activation of the tumorigenic pyrrolizidine alkaloid riddelliine, leading to DNA adduct formation in vivo. Chem Res Toxicol 2001; 14: 101-109.