Molecular basis of drug phototoxicity: photosensitized cell damage by the major photoproduct of tiaprofenic acid.
Tiaprofenic acid is a photosensitizing nonsteroidal anti-inflammatory drug, whose major photoproduct (decarboxytiaprofenic acid) is also a potent photosensitizer. Because of the lack of the carboxylate moiety, this photoproduct is more lipophilic and might bind more efficiently to cell membranes, thereby causing phototoxic damage. To verify the feasibility of this hypothesis, we have prepared the 3H-labeled analogs of tiaprofenic acid and its photoproduct and examined the binding, persistence and phototoxicity of the photoproduct using poorly metabolizing (fibroblasts) and actively metabolizing cells (hepatocytes). The photoproduct of tiaprofenic acid accumulates in both cell types as it is formed. Upon removal of the photoproduct from the culture medium, it rapidly disappears from hepatocytes but not from fibroblasts. Consequently, irradiation of fibroblasts previously incubated with the photoproduct and kept in culture in the dark for 20 h results in generalized cell damage while this effect is not observed in hepatocytes. Because of its long persistence in poorly metabolizing skin cells and its reluctance to photobleaching, the formation of this photoproduct in skin may be of relevance to explain the in vivo phototoxicity of tiaprofenic acid.
Castell
J V
JV
Centro de Investigación, Hospital Universitario La Fe (SVS), Valencia, Spain.
Gomez-Lechon
M J
MJ
Hernandez
D
D
Martinez
L A
LA
Miranda
M A
MA
D001665:Binding Sites; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011422:Propionates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D017319:Photosensitizing Agents; D011422:Propionates; C021270:tiaprofenic acid