Chlorpromazine (CPZ) is an anti-psychotic drug widely used to treat disorders such as schizophrenia or manic-depression. Unfortunately, CPZ exhibits undesirable side effects such as phototoxic and photoallergic reactions in humans. In general, the influence of drug metabolism on this type of reactions has not been previously considered in photosafety testing. Thus, the present work aims to investigate the possible photo(geno)toxic potential of drug metabolites, using CPZ as an established reference compound. In this case, the metabolites selected for the study are demethylchlorpromazine (DMCPZ), didemethylchlorpromazine (DDMCPZ) and chlorpromazine sulfoxide (CPZSO). The demethylated CPZ metabolites DMCPZ and DDMCPZ maintain identical chromophore to the parent drug. In this work, it has been found that the nature of the aminoalkyl side chain modulates the hydrophobicity and the photochemical properties (for instance, the excited state lifetimes), but it does not change the photoreactivity pattern, which is characterized by reductive photodehalogenation, triggered by homolytic carbon-chlorine bond cleavage with formation of highly reactive aryl radical intermediates. Accordingly, these metabolites are phototoxic to cells, as revealed by the 3T3 NRU assay; their photo-irritation factors are even higher than that of CPZ. The same trend is observed in photogenotoxicity studies, both with isolated and with cellular DNA, where DMCPZ and DDMCPZ are more active than CPZ itself. In summary, side-chain demethylation of CPZ, as a consequence of Phase I biotransformation, does not result a photodetoxification. Instead, it leads to metabolites that exhibit in an even enhanced photo(geno)toxicity.

中文翻译：

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脱甲基氯丙嗪代谢物的光（基因）毒性增强。

氯丙嗪（CPZ）是一种抗精神病药，广泛用于治疗精神分裂症或躁狂抑郁症等疾病。不幸的是，CPZ在人类中表现出不良的副作用，例如光毒性和光过敏反应。通常，在光安全性测试中尚未考虑过药物代谢对这类反应的影响。因此，本工作旨在研究使用CPZ作为已建立的参考化合物的药物代谢物的可能的光（遗传）毒性。在这种情况下，选择用于研究的代谢物是去甲基氯丙嗪（DMCPZ），二甲基氯丙嗪（DDMCPZ）和氯丙嗪亚砜（CPZSO）。去甲基CPZ代谢物DMCPZ和DDMCPZ保持与母体药物相同的发色团。在这项工作中，已经发现，氨基烷基侧链的性质可调节疏水性和光化学性质（例如，激发态寿命），但不会改变光反应性模式，其特征是由均相碳原子引发的还原性光脱卤作用。氯键断裂，形成高反应性的芳基自由基中间体。因此，如3T3 NRU分析所示，这些代谢产物对细胞具有光毒性。它们的光刺激因子甚至高于CPZ。在光遗传毒性研究中，无论是分离的DNA还是细胞DNA，都观察到了相同的趋势，其中DMCPZ和DDMCPZ比CPZ本身更具活性。总之，由于I期生物转化的结果，CPZ的侧链去甲基化不会导致光解毒。反而，