Vargas F, Canudas N, Miranda M A, Boscá F
Centro de Química, Instituto Venezolano de Investigaciones Cieníficas I.V.I.C., Caracas, Spain.
Photochem Photobiol. 1993 Oct;58(4):471-6. doi: 10.1111/j.1751-1097.1993.tb04917.x.
The phototoxic anti-hyperlipoproteinemic drug fenofibrate was found to be photolabile under aerobic and anaerobic conditions. Irradiation under argon of a methanol solution of this drug produced the photoproducts isopropyl 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate, 1,2-bis(4-chlorophenyl)-1,2bis (4-[isopropoxycarbonylisopropoxy]phenyl)ethane-1,2-diol and 4-(4-chlorobenzoyl)phenol, while under oxygen the photoproducts were 4-chloroperbenzoic acid, methyl 4-chlorobenzoate, 4-chlorobenzoic acid and singlet oxygen, as evidenced by trapping with 2,5-dimethylfuran. These results can be rationalized through hydrogen abstraction by excited fenofibrate, to afford a free radical as key intermediate. Biologically active antioxidants such as glutathione and cysteine efficiently reduced 4-chloroperbenzoic acid to 4-chlorobenzoic acid. The involvement of an electron transfer mechanism is suggested by detection (UV-vis spectrophotometry) of the radical cation TMP+. during the oxidation of tetramethylphenylenediamine (TMP) with 4-chloroperbenzoic acid. Fenofibrate was phototoxic in vitro when examined by the photohemolysis test, both under oxygen and argon atmosphere, although the photohemolysis rate was markedly lower under anaerobic conditions. The photoproducts 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate and 4-chloroperbenzoic acid induced hemolysis in the dark; however, this effect was quantitatively less important than photohemolysis by fenofibrate. On the other hand, fenofibrate photosensitized peroxidation of linoleic acid, monitored by the UV detection of dienic hydroperoxides. Based on the inhibition of this process upon addition of butylated hydroxyanisole, a radical chain (type I) mechanism appears to operate. In summary, fenofibrate is phototoxic in vitro. This behavior can be explained through the involvement of free radicals, singlet oxygen and stable photoproducts.
光毒性抗高脂血症药物非诺贝特在有氧和无氧条件下均被发现具有光不稳定特性。在氩气氛围下对该药物的甲醇溶液进行辐照，产生了光产物异丙基4-(1-[4-氯苯基]-1,2-二羟基)乙基苯氧基异丁酸酯、1,2-双(4-氯苯基)-1,2-双(4-[异丙氧基羰基异丙氧基]苯基)乙烷-1,2-二醇和4-(4-氯苯甲酰基)苯酚，而在氧气存在下，光产物为4-氯过苯甲酸、4-氯苯甲酸甲酯、4-氯苯甲酸和单线态氧，这通过用2,5-二甲基呋喃捕获得以证实。这些结果可以通过激发态的非诺贝特夺取氢原子来合理化解释，从而产生一个自由基作为关键中间体。生物活性抗氧化剂如谷胱甘肽和半胱氨酸能有效地将4-氯过苯甲酸还原为4-氯苯甲酸。在4-氯过苯甲酸氧化四甲基对苯二胺（TMP）的过程中，通过检测（紫外可见分光光度法）自由基阳离子TMP⁺，表明存在电子转移机制。通过光溶血试验检测发现，非诺贝特在体外具有光毒性，无论是在氧气还是氩气氛围下，尽管在厌氧条件下光溶血速率明显较低。光产物4-(1-[4-氯苯基]-1,2-二羟基)乙基苯氧基异丁酸酯和4-氯过苯甲酸在黑暗中会诱导溶血；然而，这种效应在数量上比非诺贝特的光溶血作用要小。另一方面，非诺贝特能使亚油酸发生光致过氧化反应，通过对二烯氢过氧化物的紫外检测来监测。基于添加丁基羟基茴香醚后该过程受到抑制，似乎存在自由基链（I型）机制。总之，非诺贝特在体外具有光毒性。这种行为可以通过自由基、单线态氧和稳定的光产物的参与来解释。
