Photochemical Reaction of Ketoprofen with Proteinogenic Amino Acids

Abstract

Ketoprofen (KP) is one of the most popular nonsteroidal anti-inflammatory drugs; however, drug-induced photosensitivity of KP has been reported as a serious adverse effect. KP incorporated into a protein can produce an allergen under UV irradiation, which causes drug-induced photosensitivity. The photochemistry of KP with 20 kinds of proteinogenic amino acids in phosphate buffer solutions at pH 7.4 was studied by transient absorption spectroscopy. The KP carboxylate anion (KP − ) gave rise to a carbanion via a decarboxylation within a laser pulse, and the carbanion yielded 3-ethylbenzophenone ketyl biradical (3-EBPH) through a proton transfer reaction. Twelve kinds of proteinogenic amino acids obviously accelerated the reaction. Structural information on the complexes of KP docked in the binding sites of human serum albumin (HSA) was obtained by molecular mechanics (MM) and molecular dynamics (MD) calculations. The photochemical reaction of KP − with amino acid residues in HSA was discussed on the basis of the experimental and calculational results. The information on the reactivity of KP with the amino acids and the stable structures of the KP-HSA complexes should be essential for understanding of the initial step for drug-induced photosensitivity.