Melatonin: A therapeutic potential for the neurohormone in gallbladder disorders

Abstract

In humans, N-acetyl-5-methoxytryptamine (melatonin), a neurohormone widely found in plants and animal sources, is synthesized from serotonin primarily by the pineal gland. However, it it is also produced in a number of other areas, e.g. the gastrointestinal tract. Melatonin regulates various biological and physiologic body functions and its role in the regulation of circadian rhythms, particularly, the sleep/wake cycle, is well established. Its application has brought improvements in sleep disturbances, insomnia and mental diseases e.g. depression. Furthermore, the antioxidant role of melatonin may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. Recent studies also showed that melatonin modifies immunity, stress response and certain aging processes. Additionally, it inhibits cancer cell growth in vitro and in vivo, and melatonin application has favourable effects in cancer patients. We studied the effects of melatonin in human gallbladder, as human bile and, particularly gallbladder bile, contains high physiological levels of melatonin. First, we investigated whether the melatonin receptor MT1 is present in gallbladder tissue. Expression and localization of MT1 was assessed by RT-PCR, Western blotting and immunofluorescence analysis in samples from patients with cholelithiasis and advanced gallbladder carcinoma. Additionally, we monitored mRNA expression of the two key enzymes of melatonin synthesis, i.e., arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. MT1 mRNA and protein were present in all ten cholelithiasis and five gallbladder carcinoma samples. As indicated from RT-PCR and Western blot studies, MT1 is located in gallbladder epithelium. Epithelial expression was further proven by immunofluorescence staining of MT1 in paraffin-embedded cholelithiasis and gallbladder carcinoma sections. Our results provide the first evidence for the presence of a receptor for melatonin in human gallbladder epithelia. Therefore, in addition to its profound antioxidative effects in the biliary system, melatonin might also act through MT1-mediated signal transduction pathways to regulate gallbladder function. Whether melatonin may have the potential to be useful in a clinical application for the improvement of gallbladder function in cholelithiasis patients will have to be established.