Taurine 3 pp 71-77 | Cite as

Pyrrolizidine Alkaloid-Induced Depletion of Taurine from Rat Liver In Vivo and In Vitro

  • Y. Sun
  • S. J. Hasal
  • C. C. Yan
  • K. Brendel
  • R. J. Huxtable
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 442)


Pyrrolizidine alkaloids (PAs) are a group of plant hepatotoxins13,19. Certain PAs can also cause toxicity in extra-hepatic organs, including heart, lung, kidney and the CNS. PAs produce hepatotoxicity as a result of bioactivation to the corresponding dehydroalkaloids. Dehydroalkaloids are highly reactive molecules, with half-lives of a few seconds in water7. It has been suggested that alkylation of cell macromolecules by electrophilic dehydroalkaloids is the biochemical basis of toxicity7,25. Dehydroalkaloids can also conjugate with glutathione to form 7-glutathionyl-6,7-dihydroxymethyl-5H-pyrrolizine (GSDHP), a polar detoxification product released in high concentration into the bile20. Taurine has been shown to protect against toxic exposures in liver8,23, lung5,10,16,18,31–33 and heart2–4,9. We have reported that pretreatment with taurine reduced the cardiac toxicity of the PA, monocrotaline, in rats and reduced the LD50 from 80 mg/kg to 120 mg/kg40. In this study, we report the effect of PA exposures on hepatic taurine concentration in acute, subacute and pair-feeding studies in vivo, and perfused liver and liver slice incubations in vitro.


Liver Slice Pyrrolizidine Alkaloid Taurine Level Taurine Concentration Taurine Content 
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  1. 1.
    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
  2. 2.
    Azari, J., Brumbaugh, P., and Huxtable, R.J., 1980, Prophylaxis by taurine in the hearts of cardiomyopathic hamsters, J. Mol. Cell. Cardiol., 12:1353–1366.PubMedCrossRefGoogle Scholar
  3. 3.
    Azuma, J., Sawamura, A., Awata, N., Ohta, H., Hamaguchi, T., Harada, H., Takihara, K., Hasegawa, H., Yamagami, T., Ishiyama, T., Iwata, H., and Kishimoto, S., 1985, Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial, Clin.Cardiol., 8:276–282.PubMedCrossRefGoogle Scholar
  4. 4.
    Azuma, J., Takahisa, K., Awata, N., Ohta, H., Sawamura, A., Harada, H., and Kishimoto, S., 1984, Beneficial effect of taurine on congestive heart failure induced by chronic aortic regurgitation in rabbits, Res. Comm. Chem. Pathol. Pharmacol., 45:261–270.Google Scholar
  5. 5.
    Banks, M.A., Porter, D.W., Martin, W.G., and Castranova, V., 1991, Ozone-induced lipid peroxidation and membrane leakage in isolated rat alveolar macrophages: Protective effects of taurine, J. Nutr. Biochem., 2:308–313.CrossRefGoogle Scholar
  6. 6.
    Chauvin, P., Dillon, J.-C., Moren, A., Talbak, S., and Barakaev, S., 1993, Heliotrope poisoning in Tadjikistan, Lancet, 341:1663–1663.PubMedCrossRefGoogle Scholar
  7. 7.
    Cooper, R.A. and Huxtable, R.J., 1996, A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids, Toxicon, 34:604–607.PubMedCrossRefGoogle Scholar
  8. 8.
    Dokshina, G.A., Yartsev, E.I., Kolesnikov, Y.A., and Kostesha, N.Y., 1974, Influence of taurine on the recovery of tissue respiration and oxidative phosphorylation in liver mitochondria in irradiated rats, Radiology, 14:44–48.Google Scholar
  9. 9.
    Elizarova, E.P., Orlova, T.R., and Medvedeva, N.V., 1993, Effects on heart membranes after taurine treatment in rabbits with congestive heart failure, Arzneimittelforschung, 43:308–312.PubMedGoogle Scholar
  10. 10.
    Gordon, R.E., Shaker, A.A., and Solano, D.F., 1986, Taurine protects hamster bronchioles from acute NO2-induced alterations, Am J. Pathol., 125:585–600.PubMedGoogle Scholar
  11. 11.
    Huxtable, R., Stillman, A., and Ciaramitaro, D., 1977, Characterization of alkaloids involved in human senecio (pyrrolizidine) poisoning, Proc. Western Pharmacol. Soc., 20:455–459.Google Scholar
  12. 12.
    Huxtable, R.J., 1980, Herbal teas and toxins: novel aspects of pyrrolizidine poisoning in the United States, Perspect. Biol. Med., 24:1–14.PubMedGoogle Scholar
  13. 13.
    Huxtable, R.J., 1989, Human health implications of pyrrolizidine alkaloids and herbs containing them, in: “Toxicants of Plant Origin, Vol I: Alkaloids”,. Cheeke, P.R., ed., CRC Press, Boca Raton, Florida. pp. 41–86.Google Scholar
  14. 14.
    Huxtable, R.J., 1997, Pyrrolizidine alkaloids, in: “Comprehensive Toxicology, Vol. 9. Hepatic and Gastrointestinal Toxicology”, McCuskey, R.S. and Earnest, D.L., eds., Pergamon, pp. 423-431.Google Scholar
  15. 15.
    Huxtable, R.J., Paplanus, S., and Laugharn, J., 1977, The prevention of monocrotaline-induced right ventricular hypertrophy, Chest, 71S:308–310.Google Scholar
  16. 16.
    Izumi, K., Nagata, R., Motoya, T., Yamashita, J., Hirokane, T., Nagata, T., Satoh, Y., Sawada, Y., Ishibashi, M., Yoshida, H., and Fukuda, T., 1989, Preventive effect of taurine against acute paraquat intoxication in beagles, Jpn. J. Pharmacol., 50:229–233.PubMedCrossRefGoogle Scholar
  17. 17.
    Kean, P.M. and Kay, J.M., 1965, Lung angiotensin converting enzyme activity in monocrotaline pulmonary hypertension, Thorax, 40:159.Google Scholar
  18. 18.
    Lehnert, B.E., Archuleta, D.C., Ellis, T., Session, W.S., Lehnert, N.M., Gurley, L.R., and Stavert, D.M., 1994, Lung injury following exposure of rats to relatively high mass concentrations of nitrogen dioxide, Toxicology, 89:239–277.PubMedCrossRefGoogle Scholar
  19. 19.
    Mattocks, A.R., 1986. Chemistry and Toxicology of Pyrrolizidine Alkaloids. Academic Press, London.Google Scholar
  20. 20.
    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
  21. 21.
    Mattocks, A.R. and White, I.N.H., 1973, Toxic effects and pyrrolic metabolites in the liver of young rats given the pyrrolizidine alkaloid retrorsine, Chem. Biol. Inter., 6:297–306.CrossRefGoogle Scholar
  22. 22.
    Mayer, F. and Lüthy, J., 1993, Heliotrope poisoning in Tadjikistan, Lancet, 342:246–247.PubMedCrossRefGoogle Scholar
  23. 23.
    Nakashima, T., Takino, T., and Kuriyama, K., 1982, Therapeutic effect of taurine administration on carbon tetrachloride-induced hepatic injury, Jpn. J. Pharmacol., 32:583–590.PubMedCrossRefGoogle Scholar
  24. 24.
    Parrish, A.R., Gandolfi, A.J., and Brendel, K., 1995, Precision-cut tissue slices: Applications in pharmacology and toxicology, Life Sci., 21:1887–1991.CrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Schoental, R., 1959, Liver lesions in young rats suckled by mothers treated with the pyrrolizidine (Senecio) alkaloids, lasiocarpine, and retrorsine, J. Path. Bact., 77:485–495.PubMedCrossRefGoogle Scholar
  27. 27.
    Stillman, A.E., Huxtable, R., Consroe, P., Kohnen, P., and Smith, S., 1977, Hepatic veno-occlusive disease due to pyrrolizidine poisoning in Arizona, Gastroenterology, 73:349–352.PubMedGoogle Scholar
  28. 28.
    Stuart, K.L. and Bras, G., 1956, Veno-occlusive disease of the liver in Barbados, West Indian Med. J., 5:33–36.PubMedGoogle Scholar
  29. 29.
    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, ii:271–272.CrossRefGoogle Scholar
  30. 30.
    Tandon, H.D., Tandon, B.N., and Mattocks, A.R., 1978, An epidemic of veno-occlusive disease of the liver in Afghanistan, Am. J. Gastroenterology, 70:607–613.Google Scholar
  31. 31.
    Venkatesan, N. and Chandrakasan, G., 1994, In vivo administration of taurine and niacin modulate cyclophosphamide-induced lung injury, Eur. J. Pharmacol. Environ. Toxicol. Pharmacol., 292:75–80.CrossRefGoogle Scholar
  32. 32.
    Wang, Q., Giri, S.N., Hyde, D.M., and Li, C., 1991, Amelioration of bleomycin-induced pulmonary fibrosis in hamsters by combined treatment with taurine and niacin, Biochem. Pharmacol, 42:1115–1122.PubMedCrossRefGoogle Scholar
  33. 33.
    Wang, Q., Giri, S.N., Hyde, D.M., and Nakashima, J.M., 1989, Effects of taurine on bleomycin-induced lung fibrosis in hamsters, Proc. Soc. Exp. Biol. Med., 190:330–338.PubMedCrossRefGoogle Scholar
  34. 34.
    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
  35. 35.
    Yan, C.C. and Huxtable, R.J., 1995a, Effect of the pyrrolizidine alkaloid, monocrotaline, on bile composition of the isolated, perfused rat liver, Life Sci., 57:617–626.PubMedCrossRefGoogle Scholar
  36. 36.
    Yan, C.C. and Huxtable, R.J., 1995b, Effects of the pyrrolizidine alkaloid, retrorsine, on sulfur metabolism in the liver, Proc. Western Pharmacol Soc., 38:37–40.Google Scholar
  37. 37.
    Yan, C.C. and Huxtable, R.J., 1995c, The effect of the pyrrolizidine alkaloids, monocrotaline and trichodesmine, on tissue pyrrole binding and glutathione metabolism in the rat, Toxicon, 33:627–634.PubMedCrossRefGoogle Scholar
  38. 38.
    Yan, C.C. and Huxtable, R.J., 1996a, Effect of the pyrrolizidine alkaloid monocrotaline on taurine and sulfur amino acid metabolism in the rat liver, Adv. Exp. Med. Biol., 403:135–145.PubMedGoogle Scholar
  39. 39.
    Yan, C.C. and Huxtable, R.J., 1996b, Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat, Biochem. Pharmacol., 51:375–379.PubMedCrossRefGoogle Scholar
  40. 40.
    Yan, C.C. and Huxtable, R.J., 1996c, Effects of taurine and guanidinoethane sulfonate on right ventricular hypertrophy induced by the pyrrolizidine alkaloid, monocrotaline, Biochem. Pharmacol., 51:321–329.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Y. Sun
    • 1
  • S. J. Hasal
    • 1
  • C. C. Yan
    • 1
  • K. Brendel
    • 1
  • R. J. Huxtable
    • 1
  1. 1.Department of PharmacologyUniversity of Arizona, College of MedicineTucsonUSA

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