Melatoninwithout The Hype

Aaron B. Lerner

Department of Dermatology Yale University School of Medicine New Haven, Connecticut

The melatonin project was started at Yale by Dr. Yoshiyata Takahashi and me, and completed nearly 4 years later by Dr. James Case and me. In our investigations on normal and malignant pigment cells we were studying the action of humoral and neural factors on the dispersion and aggregation of melanosomes in frog melanocytes. My research was on pigmentation at basic and clinical levels. We had just completed the isolation of a melanocyte-stimulating hormone (MSH)—a dispersing factor—from the pituitary gland. We were intrigued by a paper by McCord and Allen in 1917 in which they claimed that extracts from bovine pineal glands lightened—that is, had an aggregating action on—the color of tadpoles. We had already studied the aggregating action of adrenaline, noradrenaline and acetylcholine. Was the agent in the pineal gland of these neural chemicals? We decided to find out. No one seemed to have been interested in the report by McCord and Allen. We had no competition.

In our isolation work the first step was to lyophilize fresh frozen pineal glands from cows. We could then remove debris, connective tissue, bone fragments, etc. so that we could work with clean glands. In Figure 1 a four-year-old boy has no difficulty holding a bag with a few thousand lyophilized pineal glands. In his other hand he is holding one gland. It looks like a single piece of puffed wheat or puffed rice. By the time the project was completed Armour had sent us more than 250,000 frozen glands and we were still complaining that we needed more.

Immediately after we established the structure of melatonin we realized that this relatively small moleculae has two unusual features viz., it has one N-acetyl group and one methoxy group. Melatonin was the first methoxyindole found in mammalian tissue. It was serotonin blocked at both ends. Biologic amines such as adrenaline, noradrena-line, serotonin and histamine, all antihistamines and many tranquilizers require a nitrogen atom carrying a positive charge to be active. When acetylated their charge and biologic activity are lost. But for pigmentation in frogs removing the charge on the nitrogen greatly enhances the potency. Melatonin is 100,000 times more potent than

Figure 1.

noradrenaline, serotonin or acetylcholine in lightening frog skin. The most potent agent to darken frog skin, a-MSH, also has an N-acetyl group.

The methoxy group was of special interest. It had been assumed that indoles with methoxy groups did not exist in mammals. Hydroxyl groups on aromatic rings have a negative charge but O-methylation removes the charge. Here again removing the charge of a group results in a more potent molecule. For potency the methoxy group on the ring is more important than the acetyl group on the nitrogen. Replacing the acetyl group with a hydrogen atom so that the molecule has an amino group instead of an N-acetyl one decreases the potency of the molecule on frog pigment cells by 5 fold. However, if one puts an hydroxy group on the ring instead of a methoxy one, activity is decreased by 20,000 fold.

If one were trying to isolate melatonin today instead of 44 years ago, the bioas-say and chemical fractionations would most likely be similar to those we used. One always wonders about how many other biologically potent molecules exist, but are unknown because they are present in such small quantities and no sensitive bioassay is available to detect them.

Until 4 years ago everything went well. The research carried out by many of the participants of this meeting opened up new fields. They showed that melatonin is an important hormone especially in regard to its role related to the biologic actions of light in daily circadian and seasonal rhythms in human beings and in animals. There have been several international meetings. However in 1994 things changed. The United States Congress passed the Dietary Supplement Health and Education Act, which took herbs, vitamins, minerals, amino acids or their products out of control of the Food and Drug Administration (FDA). Also excluded from FDA regulation are compounds that are normally found in foods. Because tiny amounts of melatonin are present in foods such as bananas and rice, melatonin could be sold over the counter as a dietary supplement. In no time hype came into this field. Articles on melatonin for the lay public appeared everywhere. There were two major reports on melatonin in Newsweek magazine, including one in 1995 when it made the cover. Numerous books were published. In one year sales may have been as high as 200 million dollars. At least 10 million people have taken melatonin. Here was a hormone from a mysterious gland that could be purchased over the counter. But for what purpose? Without seeing a physician and without solid data, people could try taking melatonin for everything-to live longer, for arthritis, for immune disorders, for better sexual function, for neurologic disorders, etc. In spite of all the waste of money and of false hopes has anything good come from all this hype? Well, yes, melatonin is now inexpensive. It is relatively non-toxic. As known before this high promotion, melatonin is useful as a mild sedative and when taken properly to overcome jet-lag. For most of the other claims melatonin does not help. For a few, the jury is still out. But the mystery of the pineal gland is gone. Melatonin did help to start the modern studies of daily and seasonal biologic rhythms.

When I write about the history of melatonin I always want to say something about our research group. In the 4 years that it took to complete the melatonin project a total of only 7 people were involved, each for a period of approximately 2 years, except for the dishwasher (Kate Lehmann) and myself who were there for the entire time. Other than the dishwasher we had no technical help. By no help I mean zero. Two co-workers were postdoctoral fellows (Takahashi and Mori), one a resident (Case), one a medical student (Barkas) and one a part-time physician (Wright). Simply being a mentor for these wonderful and dedicated people was a reward in itself. Most were highly successful in academic careers. The late Dr. Yoshiyata Takahashi became Chairman of the Department of Internal Medicine at Gifu University as well as being the leading hepa-tologist in Japan. Dr. Wataru Mori rose from a fellow to being the Chairman of the Department of Pathology at the University of Tokyo. Later he became Dean of the Medical School and after that President of the University of Tokyo. He was only the second physician to become president of that University. He was the first person from Japan to be elected to the Institute of Medicine, which is part of the National Academy of Sciences. The late Dr. James Case was the first head of the Section of Dermatology at the University of Washington. Dr. Jack Barkas is at present Chairman of the Department of Psychiatry at Cornell. All got there with melatonin.

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