Involvement of drug-derived peroxides in the phototoxicity of naproxen and tiaprofenic acid.
Photodegradation of naproxen and tiaprofenic acid in aqueous buffered solutions leads to decarboxylated products with ethyl, 1-hydroxyethyl and/or acetyl side chains. The photomixtures obtained in the presence of oxygen were clearly more toxic to cultured hepatocytes than those obtained under anaerobic conditions. This effect was more noticeable in the case of naproxen. Based on the composition of the oxygenated photomixtures and the relative toxicity of the different photoproducts, it is possible to account for most of the observed toxicity in the case of tiaprofenic acid but not in the case of naproxen. This is explained as a result of the presence of drug-derived peroxidic species in the photomixtures and their contribution to the observed toxicity. Peroxides were determined by the peroxidase-catalyzed oxidation of dichlorodihydrofluorescein to its fluorescent analog. The amount of peroxides present in naproxen photomixtures was much higher than in the case of tiaprofenic acid. A dose-dependent depletion of intracellular glutathione was observed when hepatocytes were incubated with peroxide-containing naproxen photomixtures. This effect was prevented by the addition of catalase or N-acetylcysteine to the culture medium.
Castell
J V
JV
Centro de Investigación, Hospital Universitario La Fe (SVS), Valencia, Spain.
Gomez-Lechon
M J
MJ
Grassa
C
C
Martinez
L A
LA
Miranda
M A
MA
Tarrega
P
P
D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000528:radiation effects / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009288:Naproxen / Q000528:radiation effects* / Q000633:toxicity*; D010545:Peroxides / Q000633:toxicity*; D010782:Photolysis; D011422:Propionates / Q000528:radiation effects* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010545:Peroxides; D011422:Propionates; C021270:tiaprofenic acid; D009288:Naproxen