Vargas Franklin, Rivas Carlos, Díaz Yrene, Fuentes Alberto
Laboratorio de Fotoquímica, Centro de Química, Instituto Venezolano de Investigaciones Científicas I.V.I.C., Apartado 21827, Caracas 1020-A, Venezuela.
J Photochem Photobiol B. 2003 Dec 5;72(1-3):87-94. doi: 10.1016/j.jphotobiol.2003.09.010.
The phototoxic antitubercular drug pyrazinamide (1) is photolabile under irradiation with UV-A light as well as with a N2 laser (at 337 nm) in aerobic conditions. Irradiation in methanolic and in aqueous solutions of 1 produces four and three photoproducts, respectively. Their formation involves primary alpha-cleavage between the excited carbonyl of the amido group and the aromatic ring followed by hydrogen abstraction and dimerization. Pyrazinamide was able to cause photohemolysis in human erythrocytes and peroxidation of linoleic acid. Inhibition of both processes on addition of reduced glutathione (GSH) or ascorbic acid suggests the involvement of radicals. The absence of inhibition of the photohemolysis and lipid peroxidation processes in the presence of sodium azide (NaN3), or irradiation under argon, and the absence of singlet oxygen during the photolysis confirmed with 2,5-dimethylfuran rules out the possibility of participation of 1O2 in this process. Glutathione depletion was also observed. A radical intermediate was evidenced by thiobarbituric acid that was used as a radical probe, as well as by the dimerization of cysteine. No photohemolysis was detected in presence of the isolated photoproduct. We have also determined the relative efficiencies for the formation of single strand breaks after the irradiation of pBR322 DNA and pyrazinamide, which was also reduced in the presence of GSH.
光毒性抗结核药物吡嗪酰胺（1）在有氧条件下，用UV - A光以及N2激光（337nm）照射时具有光不稳定特性。在甲醇溶液和水溶液中照射1分别产生四种和三种光产物。它们的形成涉及酰胺基团的激发羰基与芳环之间的初级α - 裂解，随后是氢提取和二聚化。吡嗪酰胺能够引起人红细胞的光溶血和亚油酸的过氧化。加入还原型谷胱甘肽（GSH）或抗坏血酸后对这两个过程的抑制表明有自由基参与。在叠氮化钠（NaN3）存在下或在氩气中照射时光溶血和脂质过氧化过程无抑制作用，以及用2,5 - 二甲基呋喃证实光解过程中不存在单线态氧，排除了1O2参与此过程的可能性。还观察到谷胱甘肽耗竭。用硫代巴比妥酸作为自由基探针以及通过半胱氨酸二聚化证明了存在自由基中间体。在分离的光产物存在下未检测到光溶血。我们还测定了pBR322 DNA和吡嗪酰胺照射后形成单链断裂的相对效率，在GSH存在下该效率也降低。
