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Melatonin, a natural hormone produced by the pineal gland and also available from dietary sources, has been the target of significant research (Kolárˇ and Machácˇková, 2005). Typical food sources of melatonin include grape skins, olive oil, red wine, tomatoes, purslane, and even beer, products that dominate traditional Mediterranean cuisine (Iriti et al., 2010; Simopoulos et al., 2005). Melatonin is also found in tart cherries, walnuts, and many other common fruits and vegetables (Burkhardt et al., 2001; Reiter et al., 2007).
Studies on absorption and distribution of orally administered melatonin are limited and inconsistent. Several studies suggest melatonin is readily absorbed (Tran et al., 2009; Mistraletti et al., 2010). However, a few studies suggest < 20% of the oral dose reaches systemic circulation (Lee et al., 1995).
Research indicates the biological function and physiological significance of melatonin is more than influencing photoperiodism, circadian rhythm, and an array of hormonal systems (Reiter et al., 2005; Kolárˇ and Machácˇková, 2005; Feillet, 2010).
Studies with animals and humans indicate melatonin is synthesized in tissues in addition to the pineal gland, including the retina, gastrointestinal tract, lymphocyte, and bone marrow cells. Specific melatonin membrane receptors have been identified (Cagnacci, 1996; Reiter et al., 2007). It appears that melatonin is a signaling molecule, which through receptor-mediated GTP-binding protein (G-protein) coupling, affects the activity of numerous enzymes. These enzymes include adenyl cyclase and several phospholipases. Plasma melatonin changes with a woman’s menstrual cycle and is markedly reduced with age. While melatonin functions independently of other hormones, there is limited evidence from rodent models and primates that suggests this neuroendocrine compound may improve bone health, possibly by reducing bone resorption, decreasing osteoclastic activity, and enhancing osteoblastic activity.
Apoptosis is an essential process to prevent accumulation of cellular damage, limit cytotoxicity, and prevent cancer expression. Classical apoptosis involves either an extrinsic pathway that relies on a variety of cell surface receptors, such as tumor necrosis factor receptor family, or the intrinsic (aka mitochondrial) pathway that involves an array of Bcl-2 proapoptotic proteins present in cell membranes of the endoplasmic reticulum and outer membranes of the mitochondria. Each of these pathways relies on the activation of unique proteases called caspases (Chowdhury et al., 2008).
Melatonin may exert antiapoptotic effects on some types of cancer cells and inhibit growth and differentiation of several kinds of cell lines, such as human neuroblastoma, prostate, and even pancreatic cancer cells (Mills et al., 2005; Garcia-Santos et al., 2006; Srinivasan et al., 2008; Joo and Yoo, 2009; Leja-Szpak et al., 2010). The apparent oncostatic (cancer-fighting) effect appears to involve multiple mechanisms, which may be cancer-type specific. For example, melatonin (1 pM) may exert a pro-apoptotic effect via Bcl-2/Bax and through the expression of caspase-9 proteins. Melatonin may also inhibit the formation of unique mitogens or their metabolites by limiting the cellular uptake of linoleic acid.
Pharmacological doses of melatonin (μM and mM concentrations), and perhaps at more physiological concentrations (nM), may inhibit neuroblastoma cell growth by enhancing apoptosis through the induction of several signaling pathways and cell receptors. Melatonin can inhibit prostate cell growth through the activation of JNK (c-JUN N-terminal kinase) and inhibit the p38 kinase (modulates some inflammatory processes) through the activation of caspase-3 and activation of specific melatonin receptors (MT1) (Srinivasan et al., 2010). Melatonin also appears to directly increase natural killer cell activity and stimulate specific cytokines involved in the antiinflammatory processes.
The presence and functions of melatonin in plant foods and the dynamics of melatonin metabolism in mammals suggest this alkaloid has important physiological functions. Yet many benefits attributed to melatonin are somewhat controversial. Some suggest that melatonin does not inhibit the growth of many prostate cancer cell lines at physiological concentrations (nM), but appears to induce apoptosis of some prostate cancer cells at pharmacologic doses (~100 μM) (Pirozhok et al., 2010).
Many health benefits are associated with the consumption of Mediterranean-style diets. Clearly, a single bioactive (melatonin) or class of bioactives (polyphenols) in our food supply cannot account for the health-promoting effects independent of the nutritional balance, but our improved understanding of melatonin functions and mechanisms provides additional support for increased consumption of fruits, vegetables, nuts, and seeds.
by Roger Clemens, Dr.P.H.,
ETHorn, La Mirada, Calif.
by Wayne Bidlack, Ph.D.,
Professor, California State Polytechnic University, Pomona