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 p otent photosensitizer. Because of the lack of the carboxylate moiety, this photoproduct is more lipophilic and might bind more efficiently t o cell membranes, thereby causing phototoxic damage. To verify the fea sibility of this hypothesis, we have prepared the H-3-labeled analogs of tiaprofenic acid and its photoproduct and examined the binding, per sistence and phototoxicity of the photoproduct using poorly metabolizi ng (fibroblasts) and actively metabolizing cells (hepatocytes). The ph otoproduct 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. Conseque ntly, irradiation of fibroblasts previously incubated with the photopr oduct 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 relu ctance to photobleaching, the formation of this photoproduct in skin m ay be of relevance to explain the in vivo phototoxicity of tiaprofenic acid.