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Lung Vascular Injury from Monocrotaline Pyrrole, a Putative Hepatic Metabolite

  • Robert A. Roth
  • James F. Reindel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)

Abstract

The pyrrolizidine alkaloid, monocrotaline (MCT), is a plant toxin that causes injury to the vasculature of the lungs and pulmonary hypertension in animals. To produce lung injury, MCT is bioactivated in the liver by cytochrome P450 monooxygenases to pyrrolic metabolites which travel via the circulation to the lungs, where they cause injury by unknown mechanisms. One putative metabolite of MCT is monocrotaline pyrrole (dehydromonocrotaline, MCTP), a moderately reactive, bifunctional alkylating agent. A single, iv injection of chemically synthesized MCTP into rats causes delayed and progressive lung vascular injury and pulmonary hypertension similar to that caused by MCT itself.

Since pulmonary vascular endothelium is likely an important target of MCTP in vivo, the effects of MCTP on cultured endothelium were studied. A single application of MCTP to confluent monolayers of cultured endothelium from bovine pulmonary artery results in release of lactate dehydrogenase, some cell detachment from the growth surface and markedly altered morphology of remaining viable cells. These effects are dose-dependent and, as in vivo, are delayed in onset (1–2 days) and progressive. In endothelial cells of porcine origin, these particular responses to MCTP are also apparent but much less pronounced. Inhibition of proliferation of cells plated at low density occurred in both cell types at nominal MCTP concentrations (0.5 μg/ml) that were not overtly cytotoxic. These results indicate that MCTP causes a direct, dose-dependent injury to pulmonary vascular endothelium in culture that is delayed and progressive and suggest a mechanism by which MCT may act in vivo to cause lung injury and pulmonary hypertension.

Keywords

Pulmonary Hypertension Lung Injury Primary Pulmonary Hypertension Pyrrolizidine Alkaloid Cytochrome P450 Monooxygenases 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Adams, R., and Rogers, E. F. (1939). The structure of monocrotaline, the alkaloid in Crotalaria spectabilis and Crotalaria retusa. I. J. Am. Chem. Soc. 6, 2815–2819.CrossRefGoogle Scholar
  2. Allen, J. R., and Carstens, L. A. (1970). Pulmonary vascular occlusions initiated by endothelial lysis in monocrotaline-intoxicated rats. Exp. Mol. Pathol. 13, 159–171.CrossRefPubMedGoogle Scholar
  3. Allen, J. R., Chesney, C. F., and Frazee, W. J. (1972). Modifications of pyrrolizidine alkaloid intoxication resulting from altered hepatic microsomal enzymes. Toxicol. Appt. Pharmacol. 23, 470–479.CrossRefGoogle Scholar
  4. Bruner, L. H., Carpenter, L. J., Hamlow, P., and Roth, R. A. (1986). Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity. Toxicol. Appt. Pharmacol. 85, 416–427.CrossRefGoogle Scholar
  5. Bruner, L. H., Hilliker, K. S., and Roth, R. A. (1983). Pulmonary hypertension and EKG changes from monocrotaline pyrrole in the rat. Amer. J. Physiol. 245, H300–H306.PubMedGoogle Scholar
  6. Bruner, L. H., Johnson, K. J., Till, G. O., and Roth, R. A. (1988). Complement is not involved in monocrotaline pyrrole-induced pulmonary injury. Am. J. Physiol. 254, H258–H264.PubMedGoogle Scholar
  7. Bull, L. B., Culvenor, C. C. J., and Dick, A. T. (1968). The Pyrrolizidine Alkaloids, North-Holland, Amsterdam.Google Scholar
  8. Butler, W. H. (1970). An ultrastructural study of the pulmonary lesion induced by pyrrole derivatives of the pyrrolizidine alkaloids. J. Pathol. 102, 15–19.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. Chesney, C. F., Allen, J. R., and Hsu, I. V. (1974). Right ventricular hypertrophy in monocrotaline pyrrole treated rats. Exp. Mol. Pathol. 20, 257–268.CrossRefPubMedGoogle Scholar
  11. Furchgott, R. F. (1983). Role of the endothelium in responses of vascular smooth muscle. Circ. Res. 53, 553–557.CrossRefGoogle Scholar
  12. Ganey, P. E., Hilliker-Sprugel, K., White, S. M., Wagner, J. G., and Roth, R. A. (1988). Pulmonary hypertension due to monocrotaline pyrrole is reduced by moderate thrombocytopenia. Am. J. Physiol. 255, H1165–H1172.PubMedGoogle Scholar
  13. Ganey, P. E., and Roth, R. A. (1986). Thromboxane does not mediate pulmonary vascular response to monocrotaline pyrrole. Am. J. Physiol. 252, H743–H748.Google Scholar
  14. Ganey, P. E., Sprugel, K. H., Boner, K. E., and Roth, R. A. (1986). Monocrotaline pyrrole induced cardiopulmonary toxicity is not altered by metergoline or ketanserin. J. Pharmacol. Exp. Ther. 237, 226–231.PubMedGoogle Scholar
  15. Hammersen, F., and Hammersen, E. (1985). Some structural and functional aspects of endothelial cells. Basic Res. Cardiol. 80, 491–501.CrossRefPubMedGoogle Scholar
  16. Hanwell, A., and Linzell, J. L. (1972). Validation of the thermodilution technique for the estimation of cardiac output in the rat. Comp. Biochem. Physiol. 41, 647–657.CrossRefGoogle Scholar
  17. Hilliker, K. S., Bell, T. G., and Roth, R. A. (1982). Pneumotoxicity and thrombocytopenia after a single injection of monocrotaline. Amer. J. Physiol. 242, H573–H579.Google Scholar
  18. Hilliker, K. S., Bell, T. G., Lorimer, D., and Roth, R. A. (1984a). Effects of thrombocytopenia on monocrotaline pyrrole-induced pulmonary hypertension. Amer. J. Physiol. 246, H747–H753.Google Scholar
  19. Hilliker, K. S., Garcia, C.M., and Roth, R. A. (1983). Effects of monocrotaline and monocrotaline pyrrole on 5-hydroxytryptamine and paraquat uptake by lung slices. Res. Commun. Chem. Pathol. Pharmacol. 40, 179–197.PubMedGoogle Scholar
  20. Hilliker, K. S., Imlay, M., and Roth, R. A. (1984b). Effects of monocrotaline treatment on norepinephrine removal by isolated, perfused rat lungs. Biochem. Pharmacol. 33, 2692–2695.CrossRefGoogle Scholar
  21. Hooson, J., and Grasso, P. (1976). Cytotoxic and carcinogenic response to monocrotaline pyrrole. J. Pathol. 118, 121–129.CrossRefPubMedGoogle Scholar
  22. Huxtable, R. J. (1980). Problems with pyrrolizidine alkaloids. Trends in Pharmacol. 1, 299–303.CrossRefGoogle Scholar
  23. Karchesy, J. J., Arbogast, B., and Deinzer, M. L. (1987). Kinetics of alkylation reaction of pyrrolizidine alkaloid pyrroles. J. Org. Chem. 52, 3867–3872.CrossRefGoogle Scholar
  24. Karchesy, J. J., and Deinzer, M. L. (1981). Kinetics of alkylation reactions of pyrrolizidine alkaloid derivatives. Heterocycles 16, 631–635.CrossRefGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. Kay, J. M., and Heath, D. (1969). Crotalaria spectabilis. The Pulmonary Hypertension Plant. Charles C. Thomas, Springfield, IL.Google Scholar
  27. Kay, J. M., Smith, P., and Heath, D. (1969). Electron microscopy of Crotalaria pulmonary hypertension. Thorax 24, 511–526.CrossRefPubMedGoogle Scholar
  28. Kedzierski, B., and Buhler, D. R. (1986). The formation of 6,7-dihydro-7- hydroxyl-1- hydroxymethy1–5H-pyrrolizine, a metabolite pf pyrrolizidine alkaloids. Chem.- Biol. Interactions 57, 217–222.CrossRefGoogle Scholar
  29. Lalich, J. J., Johnson, W. D., Raczniak, T. J., and Shumaker, R. C. (1977). Fibrin thrombosis in monocrotaline pyrrole-induced cor pulmonale in rats. Arch. Pathol. Lab. Med. 101, 69–73.Google Scholar
  30. Langleben, D., and Reid, L. M. (1985). Effect of methylprednisolone on monocrotaline-induced pulmonary vascular disease and right ventricular hypertrophy. Lab. Invest. 52, 298–303.PubMedGoogle Scholar
  31. Mattocks, A. R. (1968). Toxicity of pyrrolizidine alkaloids. Nature (London) 217, 723–728.Google Scholar
  32. Mattocks, A. R. (1972). Acute hepatotoxicity of pyrrolic metabolites in rats dosed with pyrrolizidine alkaloids. Chem.-Biol. Interactions 5, 227–242.CrossRefGoogle Scholar
  33. Mattocks, A. R. (1986). Metabolism, distribution and excretion of pyrrolizidine alkaloids. In: Chemistry and Toxicology of Pyrrolizidine Alkaloids ( A.R. Mattocks, ed.), pp. 167–168. Academic Press, London.Google Scholar
  34. Mattocks, A. R., and White, I. N. H. (1970). Estimation of metabolites of pyrrolizidine alkaloids in animal tissues. Anal. Biochem. 38, 529–535.CrossRefPubMedGoogle Scholar
  35. Mattocks, A. R., and White, I. N. H. (1971). The conversion of pyrrolizidine alkaloids to N-oxides and to dihydropyrrolizidine derivatives by rat liver microsomes in vitro. Chem.-Biol. Neteract. 3, 383–396.CrossRefGoogle Scholar
  36. McLean, E. K. (1970). The toxic action of pyrrolizidine (Senecio) alkaloids. Pharmacol. Rev. 22, 429–483.Google Scholar
  37. Merkow, L., and Kleinerman, J. (1966). An electron microscopic study of pulmonary vasculitis induced by monocrotaline. Lab. Invest. 15, 547–564.PubMedGoogle Scholar
  38. Meyrick, B., and Reid, L. (1982). Crotalaria-induced pulmonary hypertension: Uptake of 3H-thymidine by the cells of the pulmonary circulation and alveolar walls. Am. J. Pathol. 106, 84–94.PubMedGoogle Scholar
  39. Molteni, A., Ward, W. F., Tsao, C-H., Port, C. D., and Solliday, N. H. (1984). Monocrotaline-induced pulmonary endothelial dysfunction in rats. Proc. Soc. Exp. Biol. Med. 176, 88–94.PubMedGoogle Scholar
  40. Neal, W. M., Rusoff, L., and Ahmann, C. F. (1935). The isolation and some properties of an alkaloid from Crotalaria spectabilis. J. Am. Chem. Soc. 57, 2560–2561.CrossRefGoogle Scholar
  41. Orlinska, U., Shaio, R.-T., Olson, J. W., and Gillespie, M. N. (1989). Detection of transforming growth factor-13 in lungs and platelets from monocrotaline-treated rats. FASEB J. 3, 903.Google Scholar
  42. Petry, T. W., Bowden, G. T., Huxtable, R. J., and Sipes, I. G. (1984). Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline. Cancer Res. 44, 1505–1509.PubMedGoogle Scholar
  43. Piercy, P. L., and Rusoff, L. L. (1946). Crotalaria spectabilis poisoning in Louisiana livestock. J. Am. Vet. Med. Assoc. 108, 69–73.PubMedGoogle Scholar
  44. Plestina, R., and Stoner, H. B. (1972). Pulmonary oedema in rats given monocrotaline pyrrole. J. Pathol. 106, 235–249.CrossRefPubMedGoogle Scholar
  45. Raczniak, T. J., Shumaker, R. C., Allen, J. R., Will, J. A., and Lalich, J. J. (1979). Pathophysiology of dehydromonocrotaline-induced pulmonary fibrosis in the beagle. Respiration 37, 252–260.CrossRefPubMedGoogle Scholar
  46. Reindel, J. F., and Roth, R. A. (1989). Pulmonary arterial endothelial cells and smooth muscle cells differ in their response to monocrotaline pyrrole (MCTP). FASEB J. 3, Al227.Google Scholar
  47. Rippetoe, P. E., Olson, J. W., Maley, B. E., and Gillespie, M. N. (1989). Epidermal growth factor-like immunoreactivity in lungs from monocrotaline-treated rats. FASEB J. 3, A903.Google Scholar
  48. Rosenberg, H. C., and Rabinovitch, M. (1988). Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am. J. Physiol. 255, H1484–H1491.PubMedGoogle Scholar
  49. Ross, R., Raines, E. W., and Bowne-Pope, D. F. (1986). The biology of platelet-derived g-rowth factor. Cell 46, 155–169.CrossRefPubMedGoogle Scholar
  50. Ross, R., and Vogel, A. (1978). The platelet-derived growth factor. Cell 14, 203–210.CrossRefPubMedGoogle Scholar
  51. Roth, R. A., and Ganey, P. E. (1987). Arachidonic acid metabolites and the mechanisms of monocrotaline pneumotoxicity. Am. Rev. Respir. Dis. 136, 762–765.CrossRefGoogle Scholar
  52. Roth, R. A., and Reindel, J. F. (1988). Response of cultured endothelial cells to monocrotaline pyrrole. FASEB J. 2, A1578.Google Scholar
  53. Roth, R. A., and Reindel, J. F., and Hoorn, C. M. (1989). Differences in sensitivity to monocrotaline pyrrole of cultured endothelium and smooth muscle cells in culture. Abstracts of the Fifth International Congress of Toxicology, Taylor and Francis, London, p. 93.Google Scholar
  54. Schoental, R., and Head, M. A. (1955). Pathologic changes in rats as a result of treatment with monocrotaline. Brit. J. Cancer 9, 229–237.CrossRefPubMedGoogle Scholar
  55. Sippe, W. L. (1964). Crotalaria spectabilis in livestock and poultry. Ann. N.Y. Acad. Sci. 111, 562–570.Google Scholar
  56. Snow, R. L., Davies, P., Pontoppidan, H., Zapol, W. M., and Reid, L. (1982). Pulmonary vascular remodelling in adult respiratory distress syndrome. Amer. Rev. Resp. Dis. 126, 887–892.Google Scholar
  57. Sugita, T., Hyers, T. M., Dauber, I. M., Wagner, W. W., McMurtry, I. F., and Reeves, T. J. (1983). Lung vessel leak precedes right ventricular hypertrophy in monocrotaline-treated rats. J. Appt. Physiol. 54, 371–374.Google Scholar
  58. Tuchweber, B., Kovaks, K., Jago, M. V., and Beaulieu, T. (1974). Effect of steroidal and non-steroidal microsomal enzyme inducers on the hepatotoxicity of the pyrrolizidine alkaloids in rats. Res. Commun. Chem. Pathol. Pharmacol. 7, 459–480.PubMedGoogle Scholar
  59. Turner, J. H., and Lalich, J. J. (1965). Experimental cor pulmonale in the rat. Arch. Pathol. 79, 409–418.PubMedGoogle Scholar
  60. Valdivia, E., Lalich, J. J., Hayashi, Y., and Songrad, J. (1967). Alterations in pulmonary alveoli after a single injection of monocrotaline. Arch. Pathol. 84, 64–76.PubMedGoogle Scholar
  61. Vane, J. R., Gryglewski, R. J., and Botting, R. M. (1987). The endothelial cell as a metabolic and endocrine organ. Trends in Pharmacol. 8, 491–496.CrossRefGoogle Scholar
  62. Vincic, L., Orr, F. W., Warner, J. A., Suyama, K. L., and Kay, J. M. (1989). Enhanced cancer metastasis after monocrotaline-induced lung injury. Toxicol. Appt. Pharmacol. 100, 259–270.CrossRefGoogle Scholar
  63. Voelkel, N., and Reeves, J. T. (1979). Primary pulmonary hypertension. In Pulmonary Vascular Diseases ( K. M. Moses, ed.), pp. 573–628. Dekker, New York.Google Scholar
  64. White, S. M., and Roth, R. A. (1988). Pulmonary platelet sequestration is increased following monocrotaline pyrrole treatment of rats. Toxicol. Appt. Pharmacol. 96, 465–475.CrossRefGoogle Scholar
  65. White, S. M., and Roth, R. A. (1989). Progressive lung injury and pulmonary hypertension from monocrotaline. In: CRC Handbook of Animal Models of Pulmonary Disease, Vol. II ( J. O. Cantor, ed.). CRC Press: Boca Raton, FL, pp. 75–91.Google Scholar
  66. 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.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Robert A. Roth
    • 1
  • James F. Reindel
    • 2
  1. 1.Departments of Pharmacology and ToxicologyMichigan State UniversityEast LansingUSA
  2. 2.Departments of PathologyMichigan State UniversityEast LansingUSA

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