Medina J, Elsaesser C, Picarles V, Grenet O, Kolopp M, Chibout S D, de Brugerolle de Fraissinette A
Preclinical Safety Department, Novartis Pharma AG, WSJ-386.1151, CH-4002 Basel, Switzerland.
In Vitr Mol Toxicol. 2001 Fall;14(3):157-68. doi: 10.1089/109793301753407920.
The goal of this study was to design a model system for the assessment of phototoxic potential using a human reconstructed epidermis (HRE, SkinEthic Laboratories, Nice, France), by testing some representative phototoxic (P) and non-phototoxic (NP) compounds and finished topical products. The tissue response to 24-h application of 5-5000 microg/mL of the test agents in the presence and absence of UVA light was analyzed in terms of viability (Lactate Dehydrogenase release), pro-inflammatory activity (IL-8 release and mRNA expression) and morphology (histopathology). 8-Methoxypsoralen (P) and promethazin (P), but not sodium lauryl sulfate (NP) produced cytotoxicity concentration-response curves significantly different between irradiated and nonirradiated tissues. Only irradiated tissues showed morphological damage. Application of tetracyclin (P) in the culture medium, but not topically, induced similar signs of phototoxicity. 6-Methylcoumarine (weak P) was not cytotoxic, yet it increased IL-8 release and mRNA expression only following UVA irradiation. PUVA therapy creams containing 1% 8-Methoxy-psoralen (P) or coal tar (P) decreased viability and induced histologic damage in UVA-exposed tissues. In conclusion, the phototoxic potential of the tested agents was correctly predicted by using a tiered strategy that involves determining cytotoxicity, production of IL-8, and morphological damage following exposure of the HRE to the compounds and UVA light.
本研究的目的是设计一个模型系统，通过测试一些具有代表性的光毒性（P）和非光毒性（NP）化合物以及成品局部用产品，利用人重建表皮（HRE，法国尼斯SkinEthic实验室）评估光毒性潜力。根据活力（乳酸脱氢酶释放）、促炎活性（IL-8释放和mRNA表达）和形态学（组织病理学）分析在有和无UVA光的情况下，将5-5000μg/mL测试剂应用24小时后组织的反应。8-甲氧基补骨脂素（P）和异丙嗪（P），但月桂醇硫酸酯钠（NP）未在照射和未照射组织之间产生显著不同的细胞毒性浓度-反应曲线。只有照射过的组织出现形态学损伤。在培养基中而非局部应用四环素（P）诱导出类似的光毒性迹象。6-甲基香豆素（弱P）无细胞毒性，但仅在UVA照射后增加IL-8释放和mRNA表达。含有1% 8-甲氧基补骨脂素（P）或煤焦油（P）的PUVA治疗乳膏降低了UVA照射组织的活力并诱导了组织学损伤。总之，通过采用一种分级策略，即确定HRE暴露于化合物和UVA光后的细胞毒性、IL-8的产生以及形态学损伤，能够正确预测测试剂的光毒性潜力。
