, Volume 49, Issue 8, pp 665–670 | Cite as

The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates

  • G. Huether
Multi-Author Reviews Melatonin and the Light-Dark Zeitgeber in Vertebrates, Invertebrates and Unicellular Organisms


While the production of melatonin in higher vertebrates occurs in other organs and tissues besides the pineal, the contribution of extrapineal sites of melatonin synthesis such as the retina, the Harderian glands and the gut to circulating melatonin levels is still a matter of debate. The amount of melatonin found in the gastrointestinal tract is much higher than in any other organ including the pineal and the gut appears to make a significant contribution to circulating melatonin at least under certain conditions. The gut has been identified to be the major source of the elevated plasma concentrations of melatonin seen after tryptophan administration and of the changes of circulating melatonin level induced by the feeding regime. Whereas the circadian and circannual fluctuations of the concentration of melatonin in the blood seem to be triggered by changes of the photoenvironment and its effect of pineal melatonin formation, basal daytime melatonin levels and the extent of their elevation at nighttime appear to be additionally controlled by nutritional factors, such as the amount and the composition of ingested food and therefore availability of tryptophan as a rate-limiting precursor of melatonin formation by the enterochromaffin cells of the gastrointestinal tract.

Key words

Melatonin pineal extrapineal Harderian glands retina gastrointestinal tract enterochromaffin cells nutrition tryptophan circadian rhythms 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Arendt, J., Melatonin. Clin. Endocr.29 (1988) 205–229.PubMedGoogle Scholar
  2. 2.
    Axelrod, J., The pineal gland: a neurochemical transducer. Science184 (1974) 1341–1348.PubMedGoogle Scholar
  3. 3.
    Balemans, M. G. M., Pévet, P., Legerstee, W. C., and Nevo, E., Preliminary investigations on melatonin and 5-methoxytryptophol synthesis in the pineal retina and Harderian gland of the mole rate and in the pineal of the mouse “eyeless”. J. neural Transm.49 (1980) 247–255.PubMedGoogle Scholar
  4. 4.
    Bertaccini, G., Tissue 5-hydroxytryptamine and urinary 5-hydroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J. Physiol.153 (1960) 239–249.Google Scholar
  5. 5.
    Biesalski, H. K., Welker, H. A., Thalmann, R., and Vollrath, L., Melatonin and other serotonin derivatives in the guinea pig membranous cochlea. Neurosci. Lett.91 (1988) 41–46.PubMedGoogle Scholar
  6. 6.
    Binkley, S., Reilly, K. B., and Hryshchyshyn, M., N-Acetyl-transferase in the chick retina: I. Circadian rhythms controlled by environmental lighting are similar to those in the pineal gland. J. comp. Physiol.139 (1980) 103–108.Google Scholar
  7. 7.
    Bojkowski, C. J., and Arendt, J., Factors influencing urinary 6-sulphatoxymelatonin, a major melatonin metabolite in normal human subjects. Clin. Endocr.33 (1990) 435–444.PubMedGoogle Scholar
  8. 8.
    Bubenik, G. A., Localization of melatonin in the digestive tract of the rat. Hormone Res.12 (1980) 313–323.PubMedGoogle Scholar
  9. 9.
    Bubenik, G. A., Brown, G., and Grota, L., Immunohistological localization of melatonin in the digestive system of the rat. Experientia33 (1977) 662–663.PubMedGoogle Scholar
  10. 10.
    Bubenik, G. A., Ball, R. O., and Pang, S. F., The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. J. pineal Res.12 (1992) 7–16.PubMedGoogle Scholar
  11. 11.
    Bubenik, G. A., and Dhanvantari, S., Influence of serotonin and melatonin on some parameters of gastrointestinal activity. J. pineal Res.7, (1989) 333–344.PubMedGoogle Scholar
  12. 12.
    Buswell, R. S., The pineal and neoplasia. Lancet I (1975) 34–35.Google Scholar
  13. 13.
    Cahill, G. M., and Besharse, J. C., Circadian regulation of melatonin in the retina ofXenopus laevis: Limitation by serotonin availability. J. Neurochem.54 (1990) 716–718.PubMedGoogle Scholar
  14. 14.
    Cardinali, D. P., and Freire, F., Melatonin effects on brain interaction with microtubule protein, inhibition of a fast axoplamic flow and induction of crystalloid and tubular formation in the hypothalamus. Mol. Cell Endocr.2 (1975) 317–330.Google Scholar
  15. 15.
    Cardinali, D. P., and Wurtman, R. J., Hydroxyindole-O-methyltransferases in rat pineal, retina and Harderian gland. Endocrinology91 (1972) 247–252.PubMedGoogle Scholar
  16. 16.
    Cho, C. H., Pang, S. F., Chen, B. W., and Pfeiffer, C. J., Modulating action of melatonin on serotonin-induced aggravation of ethanol ulceration and changes of mucosal blood flow in rat stomaches. J. pineal Res.6 (1989) 89–97.PubMedGoogle Scholar
  17. 17.
    Cogburn, L. A., Wilson-Placentra, S., and Letcher, L. R., Influence of pinealectomy on plasma and extrapineal melatonin rhythms in young chicken (Gallus domesticus). Gen. comp. Endocr.68 (1987) 343–356.PubMedGoogle Scholar
  18. 18.
    Dubocovich, M. L., Characterization of a retinal melatonin receptor. J. pharmac. exp. Ther.234 (1985) 395–401.Google Scholar
  19. 19.
    Dubocovich, M. L., Pharmacology and function of melatonin receptors. FASEB J.2 (1988) 2765–2773.PubMedGoogle Scholar
  20. 20.
    Erspamer, V., and Asero, B., Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature169 (1952) 800–801.Google Scholar
  21. 21.
    Freire, F., and Cardinali, D. P., Effects of melatonin treatment and environmental lighting on the ultrastructural appearance, melatonin synthesis, norepinephrine turnover and microtubule protein content of the rat pineal gland. J. neural. Transm.37 (1975) 237–257.PubMedGoogle Scholar
  22. 22.
    Gern, W. A., and Norris, D. O., Plasma melatonin in the neotenic tiger salamander (Ambystoma tigrinum): Effects of photoperiod and pinealectomy. Gen. comp. Endocr.38 (1979) 393–398.PubMedGoogle Scholar
  23. 23.
    Gern, W. A., Owens, D. W., and Ralph, C. L., Persistence of the nycthemeral rhythm of melatonin in pinealectomized or optic tranct-sectioned trout (Salmo gairdneri). J. exp. Zool.205 (1978) 371–376.Google Scholar
  24. 24.
    Gern, W. A., and Ralph, C. L., Melatonin synthesis by the retina. Science204 (1979) 183–184.PubMedGoogle Scholar
  25. 25.
    Halloway, W. R., Grota, I. J., Brown, G. M., Determination of immunoreactive melatonin in the colon of the rat by immunocytochemistry. J. Histochem. Cytochem.28 (1980) 255–262.PubMedGoogle Scholar
  26. 26.
    Hamm, H. E., and Menaker, M., Retinal rhythms in chicks: Circadian variation in melatonin and serotonin N-acetyltransferase activity. Proc. natl Acad. Sci.77 (1980) 4998–5002.PubMedGoogle Scholar
  27. 27.
    Harlow, H. J., and Weekly, B. I., Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestine. J. pineal Res.3 (1986) 277–284.PubMedGoogle Scholar
  28. 28.
    Huether, G., Poeggeler, B., Reimer, A., and George, A., Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci.51 (1992a) 945–953.PubMedGoogle Scholar
  29. 29.
    Huether, G., Hajak, G., Reimer, A., Poeggeler, B., Blömer, M., Rodenbeck, A., and Rüther, E., The metabolic fate of infused L-tryptophan in men: Possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites. Psychopharmacology106 (1992b) 422–432.Google Scholar
  30. 30.
    Iuvone, P. M., and Besharse, J. C., Dopamine receptor-mediated inhibition of serotonin N-acetyltransferase activity in retina. Brain Res.369 (2) (1986) 168–176.PubMedGoogle Scholar
  31. 31.
    Kennaway, D. J., Firth, R. G., Philipous, G., Matthews, C. D., Seamark, R. F., A specific radioimmunoassay for melatonin in biological tissue and fluids and its validation by gas chromatography-mass spectrometry. Endocrinology101 (1977) 119–127.PubMedGoogle Scholar
  32. 32.
    Kopin, I. J., Pare, M. B., Axelrod, J., and Weissbach, H., The fate of melatonin in animals. J. biol. Chem.236 (1961) 3072–3075.PubMedGoogle Scholar
  33. 33.
    Kopp, N., Claustrat, B., and Tappaz, M., Evidence for the presence of melatonin in the human brain. Neurosci. Lett.19 (1980) 237–242.PubMedGoogle Scholar
  34. 34.
    Krause, D. N., and Dubocovich, M. L., Regulatory sites in the melatonin system of mammals. TINS13 (1990) 464–470.PubMedGoogle Scholar
  35. 35.
    Kveder, S., and McIsaac, W. M., The metabolism of melatonin (N-acetyl-5-methoxytryptamine) and 5-methoxytryptamine. J. biol. Chem.236 (1961) 3214–3220.PubMedGoogle Scholar
  36. 36.
    Lee, P. P. N., Hong, G. X., and Pang, S. F., Melatonin in the gastrointestinal tract. In: Role of Melatonin and Pineal Peptides in Neuroimmunomodulation. Eds F. Fraschini and R. J. Reiter, Plenum Press, New York (1991) 127–138.Google Scholar
  37. 37.
    Legris, G. J., Will, P. C., and Hopfer, U., Inhibition of amiloride-sensitive serotonin conductance by indoleamines. Proc. natl Acad. Sci.79 (1982) 2046–2050.PubMedGoogle Scholar
  38. 38.
    Lerner, A. B., Case, J. D., Takahashi, Y., Lee, T. H., and Mori, N., Isolation of melatonin, a pineal factor that lightens melanocytes. J. Am. chem. Soc.80 (1958) 2587–2587.Google Scholar
  39. 39.
    Lewinski, A., Rybicka, I., Wajs, E., Szkudlinski, M., Pawlikowski, M., Influence of pineal indoleamines on the mitotic activity of gastric and colonal mucosed epithelial cells in the rat: interaction with omepazole. Pineal Res.10 (1991) 104–108.Google Scholar
  40. 40.
    Lewy, A. J., Tetsuo, M., Markey, S. P., Goodwin, F. K., Kopin, J., Pinealectomy abolishes plasma melatonin in rats. J. clin. Endocr. Metab.50 (1980) 204–205.PubMedGoogle Scholar
  41. 41.
    Neuwelt, E. A., Mickey, B., Lewy, A. J., The importance of melatonin and tumor markers in pineal tumors. J. neural Transm. (Suppl.)21 (1986) 397–413.Google Scholar
  42. 42.
    Nowak, J. Z., Zurawska, E., and Zawilska, J., Melatonin and its generating system in vertebrate retina: circadian rhythm, effect of environmental lighting and interaction with dopamine. Neurochem. Int.14 (1989) 397–406.Google Scholar
  43. 43.
    Ohisuka, H., Iwanaga, T., Hasegawa, H., Ichyama, A., and Fujita, T., Immunohistochemical localization of tryptophan hydroxylase and serotonin in the gastrointestinal tract of mice. Biomed. Res.12 (1991) 131–142.Google Scholar
  44. 44.
    Olcese, J., and Moller, M., Characterization of serotonin N-acetyltransferase activity in the retina of the mongolian gerbil,Meriones uniguiculates. Neurosci. Lett.102 (1989) 235–240.PubMedGoogle Scholar
  45. 45.
    Osol, G., Schwartz, B., and Foss, D. C., Effects of time, photoperiod, and pinealectomy on ocular and plasma melatonin concentrations in the chick. Gen. comp. Endocr.58 (1985) 415–420.PubMedGoogle Scholar
  46. 46.
    Oxenkrug, G. F., Anderson, G. F., Dragovic, L., Blavais, M., and Riederer, P., Circadian rhythms of human pineal melatonin, related indoles, and beta adrenoreceptors: Post-mortem evaluation. J. pineal. Res.9 (1990) 1–11.PubMedGoogle Scholar
  47. 47.
    Ozaki, Y., and Lynch, H. J., Presence of melatonin in plasma and urine of pinealectomized rats. Endocrinology99 (1976) 641–644.PubMedGoogle Scholar
  48. 48.
    Pang, S. F., and Brown, G. M., Regional concentrations of melatonin in the rat brain in the light and dark period. Life Sci.33 (1983) 1199–1204.PubMedGoogle Scholar
  49. 49.
    Pang, S. F., Brown, G. M., Grota, L. J., Chambers, J. W., and Rodman, R. L., Determination of N-acetylserotonin and melatonin activities in the pineal gland, retina, Harderian gland, brain and serum of rats and chickens. Neuroendocrinology23 (1977) 1–13.PubMedGoogle Scholar
  50. 50.
    Pardridge, W. M., and Mietus, L. J., Transport of albumin-bound melatonin through the blood-brain barrier. J. Neurochem.34 (1980) 1761–1763.PubMedGoogle Scholar
  51. 51.
    Pelham, R. W., Ralph, C. L., and Campbell, I. M., Mass spectral identification of melatonin in blood. Biochem. Biophys. Res. Comm.46 (1972) 1236–1241.PubMedGoogle Scholar
  52. 52.
    Penttilä, A., Histochemical reactions of the enterochromaffine cells and the 5-hydroxytryptamine content of the mammalian duodenum. Acta physiol. scand.69, Suppl. 281 (1966) 7–77.Google Scholar
  53. 53.
    Quastel, M. R., and Rahamimoff, R., Effect of melatonin on spontaneous contractions and response to 5-hydroxytryptamine of rat isolated duodenum. Br. J. Pharmac.24 (1965) 455–461.Google Scholar
  54. 54.
    Quay, W. B., and Ma, Y. H., Demonstration of gastrointestinal hydroxyindole-O-methyltransferase. Int. Rep. Clin. Sci., Med. Sci. Lib. Compend4 (1976) 563–569.Google Scholar
  55. 55.
    Raikhlin, N. T., Kvetnoy I. M., and Tolkachev, V. N., Melatonin may be synthesised in enterochromaffin cells. Nature255 (1975) 344–345.PubMedGoogle Scholar
  56. 56.
    Raikhlin, N., and Kvetnoy, I., The synthesis of melatonin in the enterochromaffin cells. Archs. Path.38 (1976) 21–25.Google Scholar
  57. 57.
    Reiter, R. J., Richardson, B. A., and Hurtbut, E. c., Pineal retinal and Harderian gland melatonin in a diurnal species, the Richardson's ground squirrel (Spermophilus richardsonii). Neurosci. Lett.22 (1981) 285–288.Google Scholar
  58. 58.
    Reiter, R. J., Richardson, B. A., Matthews, S. A., Lane, S. J., and Ferguson, B. N., Rhythms in immunoreactive melatonin in the retina Harderian gland of rats: Persistence after pinealectomy. Life Sci.32 (1983) 1229–1236.PubMedGoogle Scholar
  59. 59.
    Reiter, R. J., Pineal Melatonin: Cell Biology of its synthesis and of its physiological interactions. Endocr. Soc.2 (1991) 151–180.Google Scholar
  60. 60.
    Reppert, S. M., and Sagar, S. M., Characterization of the day-night variation of retinal melatonin content in the chick. Invest. Ophthalmol. Vis. Sci.24 (1983) 294–300.PubMedGoogle Scholar
  61. 61.
    Röjdmark, S., and Wetterberg, L., Short-term fasting inhibits the nocturnal melatonin secretion in healthy man. Clin. Endocr.30 (1989) 451–457.PubMedGoogle Scholar
  62. 62.
    Takahashi, J. S., Murakami, N., Nikaido, S. S., Pratt, B. L., and Robertson, L. M., The avian pineal, a vertebate model system of the circadian oscillator: cellular regulation of circadian rhythms by light, second messengers, and macromolecular synthesis. Recent Prog. Horm. Res.45 (1989) 279–352.PubMedGoogle Scholar
  63. 63.
    Underwood, H., Binkley, S., Siopes, T., and Mosher, K., Melatonin rhythms in the eyes, pineal bodies, and blood of Japanese Quail (Coturnis coturnix, japonica). Gen. comp. Endocr.56 (1984) 70–81.PubMedGoogle Scholar
  64. 64.
    Vakkuri, O., Rintamaki, H., and Leppaluoto, J., Presence of immunoreactive melatonin in different tissues of the pigeon (Columba livia). Gen. comp. Endocr.58 (1985a) 69–75.PubMedGoogle Scholar
  65. 65.
    Vakkuri, O., Rintamaki, H., and Leppaluoto, J., Plasma and tissue concentrations of melatonin after midnight light exposure and pinealectomy in the pigeon. J. Endocr.105 (1985b) 263–268.PubMedGoogle Scholar
  66. 66.
    Vaughan, G. M., and Reiter, R. J., Pineal dependence of the Syrian hamster's nocturnal serum melatonin surge. J. pineal Res.3 (1986) 9–14.PubMedGoogle Scholar
  67. 67.
    Welker, H. A., and Vollrath, The effect of a number of short-term exogenous stimuli on pineal serotonin-N-acetyltransferase activity in rats. J. neural. Transm.59 (1984) 68–80.Google Scholar
  68. 68.
    Wiechmann, A. F., Melatonin: parallels in pineal gland and retina. Exp. Eye Res.42 (1986) 507–527.PubMedGoogle Scholar
  69. 69.
    Wurtman, R. J., Axelrod, J. and Philips, L. S., Melatonin synthesis in the pineal gland: control by light. Science142 (1963) 1071–1073.PubMedGoogle Scholar
  70. 70.
    Yaga, K., Reiter, R. J., Richardson, B. A., Tryptophan loading increases daytime serum melatonin levels in intact and pinealectomized rats. Life Sci.52 (1993) 1231–1238.PubMedGoogle Scholar
  71. 71.
    Yu, H. S., Pang, S. F., Tang, P. L., Brown, G. M., Persistence of circadian rhythms of melatonin and N-acetylserotonin in the serum of rats after pinealectomy. Neuroendocrinology32 (1981) 262–265.PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel 1993

Authors and Affiliations

  • G. Huether
    • 1
  1. 1.Neurobiological Research UnitPsychiatrische Klinik der Universität GöttingenGöttingen(Germany)

Personalised recommendations