Department of Pharmaceutical Sciences, University of Padova , Via Marzolo 5, 35131 Padova, Italy.
Chem Res Toxicol. 2011 Aug 15;24(8):1319-26. doi: 10.1021/tx200212z. Epub 2011 Jul 15.
The photodegradation of the chemotherapeutic agent 5-fluorouracil (5-FU) under UVB light was studied both in aqueous and methanol solutions and in systemic and topical formulations. As monitored by HPLC, photodegradation in solution takes place in a concentration dependent manner; thus, the solution for parenteral administration (10(-1) M) showed negligible loss of the active principle. On the contrary, the commercial cream containing 5% of 5-FU showed low stability under UVB exposure. When dissolved either in water or methanol, 5-FU yields two photoproducts which have been characterized as two isomers coming from the addition of the solvent to the 5,6 double bond of the drug. As a consequence, photomodified 5-FU loses its antiproliferative activity on HCT-15 and HeLa cells. MS analysis showed that photoaddition occurred with nucleophilic amino acids, such as cysteine and serine, while susceptible amino acids (cysteine and methionine) were oxidized. In fact, high production of the superoxide anion under UVB light as well as photooxidation of BSA suggests protein photodamage as a mechanism of photosensitization. Indeed, some phototoxicity was shown in experiments on NCTC keratinocytes and MCF-7 resistant cells irradiated with UVB light. The interactions with these biological targets may contribute to skin phototoxicity and photoallergy induced by 5-FU in vivo.
在 UVB 光下，研究了化疗药物 5-氟尿嘧啶（5-FU）在水和甲醇溶液中的光降解以及在全身和局部制剂中的光降解。如通过 HPLC 监测，溶液中的光降解以浓度依赖的方式发生；因此，用于静脉注射的溶液（10(-1) M）几乎没有失去活性成分。相反，含有 5%5-FU 的商业乳膏在 UVB 暴露下稳定性低。当溶解在水或甲醇中时，5-FU 产生两种光产物，这些产物已被表征为两种异构体，它们是通过将溶剂添加到药物的 5,6 双键中来产生的。因此，光改性的 5-FU 失去了对 HCT-15 和 HeLa 细胞的抗增殖活性。MS 分析表明，光加成发生在亲核氨基酸（如半胱氨酸和丝氨酸）上，而易受攻击的氨基酸（半胱氨酸和蛋氨酸）被氧化。事实上，UVB 光下超氧阴离子的高产生以及 BSA 的光氧化表明蛋白质光损伤是光致敏的机制。事实上，在 NCTC 角质形成细胞和 MCF-7 耐药细胞的 UVB 光照射实验中显示出一些光毒性。与这些生物靶标的相互作用可能导致 5-FU 在体内引起皮肤光毒性和光过敏。
