Melatonin

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1: Curr Top Med Chem. 2002 Feb;2(2):181-97. Related Articles,

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Chemical and physical properties and potential mechanisms: melatonin

as a broad spectrum antioxidant and free radical scavenger.

Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo

JC, Kohen R, Allegra M, Hardeland R.

Department of Cellular and Structural Biology, University of Texas

Health Science Center, San 78229-3900, USA.

Melatonin was found to be a potent free radical scavenger in 1993.

Since then over 800 publications have directly or indirectly

confirmed this observation. Melatonin scavenges a variety of

reactive oxygen and nitrogen species including hydroxyl radical,

hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite

anion. Based on the analyses of structure-activity relationships,

the indole moiety of the melatonin molecule is the reactive center

of interaction with oxidants due to its high resonance stability and

very low activation energy barrier towards the free radical

reactions. However, the methoxy and amide side chains also

contribute significantly to melatonin's antioxidant capacity. The N-

C=O structure in the C3 amide side chain is the functional group.

The carbonyl group in the structure of N-C=O is key for melatonin to

scavenge the second reactive species and the nitrogen in the N-C=O

structure is necessary for melatonin to form the new five membered

ring after melatonin's interaction with a reactive species. The

methoxy group in C5 appears to keep melatonin from exhibiting

prooxidative activity. If the methoxy group is replaced by a

hydroxyl group, under some in vitro conditions, the antioxidant

capacity of this molecule may be enhanced. However, the cost of this

change are decreased lipophility and increased prooxidative

potential. Therefore, in in vivo studies the antioxidant efficacy of

melatonin appears to be superior to its hydroxylated counterpart.

The mechanisms of melatonin's interaction with reactive species

probably involves donation of an electron to form the melatoninyl

cation radical or through an radical addition at the site C3. Other

possibilities include hydrogen donation from the nitrogen atom or

substitution at position C2, C4 and C7 and nitrosation. Melatonin

also has the ability to repair damaged biomolecules as shown by the

fact that it converts the guanosine radical to guanosine by electron

transfer. Unlike the classical antioxidants, melatonin is devoid of

prooxidative activity and all known intermediates generated by the

interaction of melatonin with reactive species are also free radical

scavengers. This phenomenon is defined as the free radical

scavenging cascade reaction of the melatonin family. Due to this

cascade, one melatonin molecule has the potential to scavenge up to

4 or more reactive species. This makes melatonin very effective as

an antioxidant. Under in vivo conditions, melatonin is often several

times more potent than vitamin C and E in protecting tissues from

oxidative injury when compared at an equivalent dosage

(micromol/kg). Future research in the field of melatonin as a free

radical scavenger might be focused on: 1), signal transduction and

antioxidant enzyme gene expression induced by melatonin and its

metabolites, 2), melatonin levels in tissues and in cells, 3),

melatonin structure modifications, 4), melatonin and its metabolites

in plants and, 5), clinical trials using melatonin to treat free

radical related diseases such as Alzheimer's, Parkinson's, stroke

and heart disease.

Publication Types:

Review

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PMID: 11899100 [PubMed - indexed for MEDLINE]

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