Chemiexcited Neurotransmitters and Hormones Create DNA Photoproducts in the Dark

Abstract

In DNA, electron excitation allows adjacent pyrimidine bases to dimerize by [2 + 2] cycloaddition, creating chemically stable but lethal and mutagenic cyclobutane pyrimidine dimers (CPDs). The usual cause is ultraviolet radiation. Alternatively, CPDs can be made in the dark (dCPDs) via chemically mediated electron excitation of the skin pigment melanin, after it is oxidized by peroxynitrite formed from the stressinduced radicals superoxide and nitric oxide. We now show that the dark process is not limited to the unusual structural molecule melanin: signaling biomolecules such as indolamine and catecholamine neurotransmitters and hormones can also be chemiexcited to energy levels high enough to form dCPDs. Oxidation of serotonin, dopamine, melatonin, and related biogenic amines by peroxynitrite created triplet-excited species, evidenced by chemiluminescence, energy transfer to a triplet-state reporter, or transfer to O 2 resulting in singlet molecular oxygen. For a subset of these signaling molecules, triplet states created by peroxynitrite or peroxidase generated dCPDs at levels comparable to ultraviolet (UV). Neurotransmitter catabolism by monoamine oxidase also generated dCPDs. These results reveal a large class of signaling molecules as electronically excitable by biochemical reactions and thus potential players in deviant mammalian metabolism in the absence of light.

Plasmalogen oxidation induces the generation of excited molecules and electrophilic lipid species

“…Notably, excited molecules can propagate oxidative reaction in the absence of light, a phenomenon known as “dark photochemistry” (26, 41). Additionally, triplet carbonyls can cause deleterious effects in cells by transferring energy to other biomolecules, a process recently described for excited melanin, neurotransmitters, and hormones, leading to the formation of carcinogenic DNA modifications (49, 50). Hence, triplet carbonyl emerges as a product of plasmalogen oxidation with deleterious action.…”

Plasmalogen oxidation induces the generation of excited molecules and electrophilic lipid species

“…Notably, excited molecules can propagate oxidative reaction in the absence of light, a phenomenon known as “dark photochemistry” ( 27 , 42 ). Additionally, triplet carbonyls can cause deleterious effects in cells by transferring energy to other biomolecules, a process recently described for excited melanin, neurotransmitters, and hormones, leading to the formation of carcinogenic DNA modifications ( 26 , 50 ). Hence, excited triplet carbonyl species emerges as a product of plasmalogen oxidation with deleterious action.…”

Endogenous Photosensitizers in Human Skin

“…Chemiexcited neurotransmitters and hormones have also been shown to create DNA photoproducts in the dark. 684 Lipids also encompass important examples of antioxidant compounds that efficiently inhibit lipid peroxidation in general. Vitamin E is the major protector of lipids and membranes in any cell/tissue with very important roles in skin homeostasis, especially concerning protection against constant exposoma challenges on the skin.…”

“…However, even in the absence of all three factors, peroxidation reactions can persist via the generation of radicals or excited states through energy transfer, an effect that has been referred to as “photochemistry in the dark”. , The biological consequences of these photoinduced and subsequent dark oxidations can persist for long periods, through the generation of other bioactive compounds, such as aldehydes, ketones, alcohols, and furans. Chemiexcited neurotransmitters and hormones have also been shown to create DNA photoproducts in the dark …”