Neurochemical Research

, Volume 21, Issue 2, pp 141–146 | Cite as

Physicochemical and metabolic basis for the differing neurotoxicity of the pyrrolizidine alkaloids, trichodesmine and monocrotaline

  • R. J. Huxtable
  • C. C. Yan
  • S. Wild
  • S. Maxwell
  • R. Cooper
Original Articles


Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD50 57 μmol/kg) and monocrotaline pneumotoxic (LD50 335 μmol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to highly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver into perfusate on perfusion for 1 hr with 0.5 mM of the parent PA. Dehydrotrichodesmine had a significantly longer aqueous half-life (5.4 sec) than that of dehydromonocrotaline (3.4 sec). In vivo, significantly higher levels of bound pyrroles were found in the brain 18 hr after injection of trichodesmine (25 mg/kg; i.p) than were seen following either an equal dose (25 mg/kg; i.p.) or an equitoxic dose (90 mg/kg; i.p.) of monocrotaline. Trichodesmine had a higher partition coefficient than monocrotaline for both chloroform and heptane, indicating its greater lipophilicity. The pKa of trichodesmine (7.07) was only slightly higher than that of monocrotaline (pKa 6.83), suggesting that a difference in degree of ionization was not a major factor affecting the relative ability of the dehydroalkaloids to cross the blood-brain barrier. We conclude that the greater lethality and neurotoxicity of trichodesmine compared to monocrotaline is due to two structural characteristics: (i) steric hindrance at position 14 of dehydrotrichodesmine results in greater resistance to hydrolysis, allowing more to be released from the liver and to be delivered to the brain; (ii) the larger isopropyl substituent at position 14 of dehydrotrichodesmine renders the molecule more lipophilic, leading to greater penetration of the brain.

Key Words

Pyrrolizidine alkaloids monocrotaline trichodesmine neurotoxicity 


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  1. 1.
    Mattocks, A.R. (1986). Chemistry and Toxicology of Pyrrolizidine Alkaloids, Academic Press, London.Google Scholar
  2. 2.
    Smith, L.W., and Culvenor, C.C.J. 1981. Plant sources of hepatotoxic pyrrolizidine alkaloids, J. Nat. Prod. 44:129–152.PubMedCrossRefGoogle Scholar
  3. 3.
    Robins D.J. (1982). The pyrrolizidine alkaloids, Fortschr. Chem. Org. Naturst, 41:115–203.PubMedGoogle Scholar
  4. 4.
    Huxtable R.J. (1989). Human health implications of pyrrolizidine alkaloids and herbs containing them. Pages 41–86,in Cheeke, P.R. (ed.), Toxicants of Plant Origin, Vol I: Alkaloids, CRC Press, Boca Raton, Florida.Google Scholar
  5. 5.
    Huxtable, R.J. (1993). Hepatic nonaltruism and pulmonary toxicity of pyrrolizidine alkaloids. Pages 215–239,in Gram, T.E. (ed.), Metabolic Activation and Toxicity of Chemical Agents to Lung Tissue and Cells, Pergamon Press, New York.Google Scholar
  6. 6.
    Mattocks A.R. 1972. Acute hepatotoxicity and pyrrolic metabolites in rats dosed with pyrrolizidine alkaloids. Chem.-Biol. Interact. 5:227–242.PubMedCrossRefGoogle Scholar
  7. 7.
    Huxtable R.J., and Wild S.L. 1994. Relationship between in vitro metabolism of pyrrolizidine alkaloids and extrahepatic toxicity in vivo, Proc. Western Pharmacol. Soc. 37:109–111.Google Scholar
  8. 8.
    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. Disp. 17:387–392.Google Scholar
  9. 9.
    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.PubMedGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Candrian U., Luthy J., and Schlatter C. 1985. In vivo covalent binding of retronecine-labelled [3H]seneciphylline and [3H]senecionine to DNA of rat liver, lung and kidney, Chem.-Biol. Interact. 54:57–69.PubMedCrossRefGoogle Scholar
  12. 12.
    Huxtable R.J., Bowers R., Mattocks A.R., and Michnicka M. 1991. Sulfur conjugates as putative pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline. Pages 605–612,in Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., and Sipes, I.G. (eds.), Biological Reactive Intermediates Vol. IV: Molecular and Cellular Effects and their Impact on Human Health, Plenum Press, New York.Google Scholar
  13. 13.
    Culvenor, C.C.J., Dann A.T., and Dick A.T. 1962. Alkylation as the mechanism by which the hepatotoxic pyrrolizidine alkaloids act on cell nuclei, Nature (London), 195:570–573.CrossRefGoogle Scholar
  14. 14.
    Mattocks A.R., Croswell S., Jukes R., and Huxtable R.J. 1991. Identity of a biliary metabolite formed from monocrotaline in isolated, perfused rat liver, Toxicon. 29:409–415.PubMedCrossRefGoogle Scholar
  15. 15.
    Adams R., and Rogers E.F. 1939. The structure of monocrotaline, the alkaloid in Crotalaria spectabilis and Crotalaria retusa, J. Amer. Chem. Soc. 61:2815–2819.CrossRefGoogle Scholar
  16. 16.
    Mattocks A.R., Jukes R., and Brown J. 1989. Simple procedures for preparing putative toxic metabolites of pyrrolizidine alkaloids, Toxicon, 27:561–567.PubMedCrossRefGoogle Scholar
  17. 17.
    Yan C.C., and Huxtable R.J. 1994. Quantitation of the hepatic release of metabolites of the pyrrolizidine alkaloid, monocrotaline, Toxicol. Appl. Pharmacol. 127:58–63.PubMedCrossRefGoogle Scholar
  18. 18.
    Mattocks A.R., and White I.N.H. 1970. Estimation of metabolites of pyrrolizidine alkaloids in animal tissues, Anal. Biochem. 38:529–535.PubMedCrossRefGoogle Scholar
  19. 19.
    Yan C.C., and Huxtable R.J. 1995. Relationship between glutathione concentration and metabolism of the pyrrolizidine alkaloid, monocrotaline, in the isolated, perfused liver, Toxicol. Appl. Pharmacol. 130:132–139.PubMedCrossRefGoogle Scholar
  20. 20.
    Robertson K.A. 1982. Alkylation of N2 in deoxyguanosine by dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline, Cancer Res. 42:8–14.PubMedGoogle Scholar
  21. 21.
    Niwa H., Ogawa T., Okamoto O., and Yamada K. 1991. Alkylation of nucleosides by dehydromonocrotaline, the putative toxic metabolite of the carcinogenic pyrrolizidine alkaloid monocrotaline, Tetrahedron Letters, 32:927–930.CrossRefGoogle Scholar
  22. 22.
    Petry T., Bowden G.T., Huxtable R.J. and Sipes I.G. 1984. Characterization of hepatic DNA damage induced by the pyrrolizidine alkaloid monocrotaline, Cancer Res. 44:1505–1509.PubMedGoogle Scholar
  23. 23.
    Kay, J.M., and D. Heath 1969. Crotalaria Spectabilis: The Pulmonary Hypertension Plant, Thomas, Springfield, IL.Google Scholar
  24. 24.
    Huxtable R.J. 1990. Activation and pulmonary toxicity of pyrrolizidine alkaloids, Pharmacology and Therapeutics, 47:371–389.PubMedCrossRefGoogle Scholar
  25. 25.
    Hayashi, Y. and J.J. Lalich 1967. Renal and pulmonary alterations induced in rats by a single injection of monocrotaline, Proc. Soc. Exp. Biol. Med. 124:392–396. (Abstract)PubMedGoogle Scholar
  26. 26.
    Carrillo L., and Aviado D. 1969. Monocrotaline-induced pulmonary hypertension and p-chlorophenylalanine (PCPA), Laboratory Investigation, 20:243–248.PubMedGoogle Scholar
  27. 27.
    Blaustein M.P. 1988. Calcium transport and buffering in neurons, Trends Neurol. Sci. 11:438–443.CrossRefGoogle Scholar
  28. 28.
    Ismailov N.I., Madzhidov N.M., Magrupov A.L., Makhkamov G.M., and Mukminova S. 1970. Clinical signs, diagnosis and treatment of Trichodesma toxicosis (alimentary toxic encephalopathy), Meditsina (Tashkent, Uzbek SSR), 85Google Scholar
  29. 29.
    IARC 1975. Pyrrolizidine alkaloids, IARC Monograph, 10:265–343.Google Scholar
  30. 30.
    Glowaz S.L., Michnika M. and Huxtable R.J. 1992. Detection of a reactive pyrrole in the hepatic metabolism of the pyrrolizidine alkaloid, monocrotaline, Toxicol. Appl. Pharmacol. 115:168–173.PubMedCrossRefGoogle Scholar
  31. 31.
    Mattocks A.R. 1968. Toxicity of pyrrolizidine alkaloids, Nature (London), 217:723–728.CrossRefGoogle Scholar
  32. 32.
    Yan C.C. and Huxtable R.J. 1995. The relationship between the concentration of the pyrrolizidine alkaloid monocrotaline and the pattern of metabolites released from the isolated liver, Toxicol. Appl. Pharmacol. 130:1–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Cooper R.A. and Huxtable R.J. 1996. A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids Toxicon, in press.Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • R. J. Huxtable
    • 1
  • C. C. Yan
    • 1
  • S. Wild
    • 1
  • S. Maxwell
    • 1
  • R. Cooper
    • 1
  1. 1.Department of PharmacologyUniversity of Arizona College of MedicineTucson

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