Abstract
During the past decade L-tryptophan (Trp) ingestion have been associated with a multi-systemic syndrome, known as eosinophilia myalgia syndrome (EMS). Even though an epidemic studies indicated that a contaminant 1,1′-ethylidene-bis-L-tryptophan was involved in EMS, abnormalities in metabolism of Trp have been reported in other similar clinical syndromes such as carcinoid syndrome, scleroderma or eosinophilic fasciitis.
The purpose of the study was to investigate the role of Trp or its metabolite, given in different dosing regimens in induction of tissue damage.
Method: 3 months old female rats (Charles River CD-1) were fed for 3,6,12 weeks on a diet containing 20% protein diet derived from casein and supplemented with 1%, 2%, or 5% Trp. On the last week of feeding, half of the animals fed on a control diet and half of the animals fed on the Trp diet were injected with 2 injections of para-chlorophenyl alanine (p-CPA), a Trp hydroxylase inhibitor, 300mg/kg i.p followed by 3 injection of 100 mg/kg every alternate day.
Results: Body weight of rats fed higher levels of Trp increased slowly and injection of p-CPA induced loss in body weight. 2/6 of the animals treated with 1% Trp and 1/6 treated with 5% Trp for 3 weeks and 2/4 animals treated with 1% Trp and 1/4 treated with 5% Trp for 12 weeks died after injection of p-CPA. No mortality was detected in 1-5% Trp treated animals. Alopecia and skin changes were seen after p-CPA in 1-5% Trp treated animals. Increased amounts of connective tissue and induction of inflammatory cell proliferation were observed in lung, spleen and in gastrocnemia muscle of rats treated with higher dose of Trp for longer period. Induction of kynurenine pathway by injection of p-CPA caused more tissue damage.
It is concluded that excessive Trp or elevation of its metabolites could play a role in amplifying some of pathological features of EMS. This pathological damage is further augmented by metabolites of the kynurenine pathway.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Anderson, I. and Cowen, P., 1991, Neuroendocrine responses to L-tryptophan as an index of brain serotonin function: effect of weight loss. Kynurenine and serotonin pathways. Adv. Exp. Med. Biol. 294:245–254.
Arzt, E., Costas, M., Finkielman, S.V., and Nahman, E., 1991, Serotonin inhibition of tumor necrosis factor-α synthesis by human monocytes. Life Science. 48:2557–2562.
Bruce, V.P., Werth, A.H., Rook, C.R., and Schumacher, O., 1990, L-tryptophan ingestion associated with eosinophilic fasccitis but not with progressive systemic sclerosis. Ann. Int. Med. 112:758–762.
Cooper, J.R., Bloom, F.E., and Roth, R.H., 1991, The Biochemical Basis of Neuropharmacology, 6th ed., Oxford University Press, p. 338-380.
Duffy, J, 1992, The lessons of Eosinophilia-Myalgia Syndrome. Hospital Practice 30:65–90.
Freese, J., Kenton, B.A., and Swartz, J., Mattew, 1990, Kynurenine metabolites of tryptophan: Implications for neurologic diseases. Neurology 40:691–695.
Freis, J.F., Lingren, J.A., and Bull, M.J., 1973, Scleroderma-like lesions and Carcinoid syndrome. Arch. Intern. Med. 131:550–552.
Heyes, M.P., Saito, K., and Crowley, J.S., 1992a, Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurologic disease. Brain. 115:1249–1273.
Heyes, M.P., Saito, K., and Markey, S.P., 1992b, Human macrophges convert L-tryptophan into the neurotoxin quinolinic acid. Biochem. J. 283:633–635.
Lee, S.L., Wang, W., Lanzillo, J.J., and Fanburg, B.L., 1994, Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cell in culture. Am. J. Physiol. 266:L46–L52.
Leonhardt, A.B., Neal, J.W., Kuln, J.A., Schwarz, M, and Plimmer, J.R., 1986, Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 219:316–318.
Livne, E., Ronen, N., Mokady, S., Reznick, A.Z., and Gross, B., 1998, Oxidative damage in rat skeletal muscle after excessive L-tryptophan and atherogenic diet. In “Oxidative stress in skeletal muscle” (Reznick A.Z, Packer L, Sen C.K. Eds) Birkhauser Verlag press, pp. 257–271.
Love, A.L., Rader, J.I., Corfford, L.J., Page, S.W., Trucksess, M.W, Smith, M.J., and Turner, M.L., 1993, Pathological and immunological effects of ingesting L-tryptophan and 1,1′-ethylidenebis (L-tryptophan) in Lewis rats. J. Clin. Invest. 91:804–811.
Mayeno, A.N., Lin, S., Fode, C.S., Loegering, D.A., Ames, N.M., Hedberg, C.W., and Gleich, G.J., 1990, Characterization of “peak E”, a novel amino acid associated with EMS. Science 250:1707–1708.
Meyer, K.C., Arend, R.A., Kalayoglu, M.V., Rosenthal, N.S., Byrne, G.I., and Brown, R.R., 1995, Tryptophan metabolism in chronic inflammatory lung disease. J. Lab. Clin. Med. 126:530–540.
Pakala, R., Willerson, J.T., Benedict, C.R., 1994, Mitogen effect of serotonin on vascular endothelial cells. Circulation 90:1919–1926.
Ronen, N., Gross, B., Ben-Shachar, D., and Livne, E. 1996, The effects of induced kynurenine pathway on immunocytochemical changes in rat tissues following excessive L-tryptophan consumption. Adv. Exp. Med. Biol. 398:177–182.
Saito, K., Crowley, J.S., Markry, S.P., and Heyes, M.P., 1993, A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J. Biol. Chem. 268:15496–15503.
Silver, R.M., Ludwicka, A., Hampton, M., Ohba, T., Bingel, S., Smith, T., Russell, A.H., Maize, J., and Heyes, M.P., 1994, A murine model of the EMS induced by 1′1″-ethylidenebis L-tryptophan. J. Clin. Invest. 93:1473–1480.
Smith, S.A., Roelofs, R.I., and Gertner, E., 1990 Microangiopathy in eosinophilia-myalgia syndrome. J. Rheumatol. 17:1544–1550.
Sterenberg, E.M., Vav Woert, M.H., Young, S.N., and Magnussen, I.B., 1980, Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa. New. Engl. J. Med. 303:782–787.
Varesio, L., Calyton, M., Ruffman, E., and Radzioch, D., 1990, Picolonic acid, a catabolite of tryptophan, as the second signal in the activation of interferon-γ-primed macrophages J. Immunol. 145:4265–4271.
Varesio, L., Soleti, A., Radzioch, D., Pulkki, K., Brooks, A., Gusella, G.L., Bosco, M.C., and Forni, G., 1994, Picolinic acid and its influence on the immune system. In: L-tryptophan current prospects in medicine and drug safty (Kochen W. and Steinhart H. eds) Walter de Gruyter press, Berlin pp. 99–110.
Varga, J., Peltonen, J., and Uitto, S., Jimenez, 1990, Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: Demonstration of Elevated Type I Collagen gene expression in affected tissues. Ann. Int. Med. 112:344–351.
Young, M.R.I. and Matthews, J.P., 1995, Serotonin regulation of T-cell sub populations and macrophage accessory function. Immunol. 84:148–152.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Gross, B., Ronen, N., Honigman, S., Livne, E. (1999). Tryptophan Toxicity—Time and Dose Response in Rats. In: Huether, G., Kochen, W., Simat, T.J., Steinhart, H. (eds) Tryptophan, Serotonin, and Melatonin. Advances in Experimental Medicine and Biology, vol 467. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4709-9_63
Download citation
DOI: https://doi.org/10.1007/978-1-4615-4709-9_63
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7133-5
Online ISBN: 978-1-4615-4709-9
eBook Packages: Springer Book Archive