Toxicology of Blister Agents: Is Melatonin a Potential Therapeutic Option?

Abstract

Blister or vesicant chemical warfare agents (CWAs) have been widely used in different military conflicts, including World War I and the Iran-Iraq War. However, their mechanism of action is not fully understood. Sulfur and nitrogen mustard exert toxic effects not only through the alkylation of thiol-bearing macromolecules, such as DNA and proteins, but also produce free radicals that can develop direct toxic effects in target organs such as the eyes, skin, and respiratory system. The lack of effective treatments against vesicant CWAs-induced injury makes us consider, in this complex scenario, the use and development of melatonin-based therapeutic strategies. This multifunctional indoleamine could facilitate neutralization of the oxidative stress, modulate the inflammatory response, and prevent the DNA damage, as well as the long-term health consequences mediated by vesicant CWAs-induced epigenetic mechanisms. In this context, it would be essential to develop new galenic formulations for the use of orally and/or topically applied melatonin for the prophylaxis against vesicant CWAs, as well as the development of post-exposure treatments in the near future.

Keywords: DNA damage; galenic formulation; inflammation; melatonin; oxidative stress; safety; sulfur and nitrogen mustard.

Figure 1

Chemical structure of the most representative blister agents.

Figure 2

Summary of the cellular and molecular mechanisms displayed by melatonin against vesicant chemical warfare agents (CWAs).

Scheme 1

Three alternative free radical-mediated mechanisms for quenching the nitrogen mustard toxic agent exerted by melatonin.

Scheme 2

First cyclization reaction that forms the highly electrophilic ammonium cation. Melatonin prevents this cation by alternatively forming the less toxic N-methylaziridine (a HAT-type mechanism is represented as an example).

Scheme 3

Formation of reactive nitrogen mustard and interaction with guanine in DNA. Melatonin would be able to trap the ammonium cation, avoiding such adduct formation.

Scheme 4

Second cyclization and alkylation of complementary DNA base resulting in a DNA crosslink.