title: UV-photoconversion of ethosuximide from a longevity-promoting compound to a potent toxin.
abstract: The anticonvulsant ethosuximide has been previously shown to increase life span and promote healthspan in the nematode Caenorhabditis elegans at millimolar concentrations. Here we report that following exposure to ultraviolet irradiation at 254 nm, ethosuximide is converted into a compound that displays toxicity toward C. elegans. This effect is specific for ethosuximide, as the structurally related compounds trimethadione and succinimide do not show similar toxicities following UV exposure. Killing by UV-irradiated ethosuximide is not attenuated in chemosensory mutants that are resistant to toxicity associated with high doses of non-irradiated ethosuximide. Non-irradiated ethosuximide extends life span at 15°C or 20°C, but not at 25°C, while irradiated ethosuximide shows similar toxicity at all three temperatures. Dietary restriction by bacterial deprivation does not protect against toxicity from irradiated ethosuximide, while non-irradiated ethosuximide further extends the long life spans of restricted animals. These data support the model that ethosuximide extends life span by a mechanism that is, at least partially, distinct from dietary restriction by bacterial deprivation and demonstrates an unexpected photochemical conversion of ethosuximide into a toxic compound by UV light.
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Haeri
authors: H
authors: Choi
authors: Heather
authors: H
authors: Schneider
authors: Shannon
authors: S
authors: Klum
authors: Devon
authors: D
authors: Chandler-Brown
authors: Matt
authors: M
authors: Kaeberlein
authors: Lara
authors: L
authors: Shamieh
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000378:metabolism*; D005013:Ethosuximide / Q000009:adverse effects* / Q000494:pharmacology; D005508:Food Deprivation; D008136:Longevity / Q000187:drug effects* / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D005013:Ethosuximide