Extrapineal melatonin: sources, regulation, and potential functions

Abstract

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Fig. 1

Daily changes in the melatonin levels of membrane, cytosol, mitochondria, and nuclei from rat cerebral cortex of sham-operated (SPx) and pinealectomized (Px) rats. Animals were maintained in a 12:12 h cycle and killed at the indicated hours. Black bars indicate the night period. ** p < 0.01 and *** p < 0.001 vs. SPx

Fig. 2

Daily changes in the melatonin content of membranes, cytosol, mitochondria, and nuclei from rat liver of sham-operated (SPx) and pinealectomized (Px) rats. Animals were maintained in a 12:12 h cycle and killed at the indicated hours. Black bar indicates the night period. *p < 0.05, **p < 0.01, and ***p < 0.001 vs. SPx

Fig. 3

Most of the melatonin present in extrapineal tissues is produced locally for regulatory processes. This melatonin may act via intracrine, autocrine, or paracrine mechanisms to maintain cell homeostasis

Fig. 4

Dose-dependent changes in the subcellular distribution of melatonin in rat liver. Control rats were intraperitoneally injected with either vehicle (0) or 10, 40, 100, or 200 mg/kg melatonin at 10:00 h, and killed 2 h later. *p < 0.05, and ***p < 0.001 vs. 0