Beiersdorf AG, Unnastraße 48, D-20253, Hamburg, Germany.
TissUse GmbH, Oudenarder Str. 16, D-13347, Berlin, Germany.
Toxicology. 2021 Jan 30;448:152637. doi: 10.1016/j.tox.2020.152637. Epub 2020 Nov 18.
Microphysiological systems (MPS) aim to mimic the dynamic microenvironment and the interaction between tissues. While MPS exist for investigating pharmaceuticals, the applicability of MPS for cosmetics ingredients is yet to be evaluated. The HUMIMIC Chip2 ("Chip2″), is the first multi-organ chip technology to incorporate skin models, allowing for the topical route to be tested. Therefore, we have used this model to analyze the impact of different exposure scenarios on the pharmacokinetics and pharmacodynamics of two topically exposed chemicals, hyperforin and permethrin. The Chip2 incorporated reconstructed human epidermis models (EpiDerm™) and HepaRG-stellate spheroids. Initial experiments using static incubations of single organoids helped determine the optimal dose. In the Chip2 studies, parent and metabolites were analyzed in the circuit over 5 days after application of single and repeated topical or systemic doses. The gene expression of relevant xenobiotic metabolizing enzymes in liver spheroids was measured to reflect toxicodynamics effects of the compounds in liver. The results show that 1) metabolic capacities of EpiDerm™ and liver spheroids were maintained over five days; 2) EpiDerm™ model barrier function remained intact; 3) repeated application of compounds resulted in higher concentrations of parent chemicals and most metabolites compared to single application; 4) compound-specific gene induction e.g. induction of CYP3A4 by hyperforin depended on the application route and frequency; 5) different routes of application influenced the systemic concentrations of both parents and metabolites in the chip over the course of the experiment; 6) there was excellent intra- and inter-lab reproducibility. For permethrin, a process similar to the excretion in a human in vivo study could be simulated which was remarkably comparable to the in vivo situation. These results support the use of the Chip2 model to provide information on parent and metabolite disposition that may be relevant to risk assessment of topically applied cosmetics ingredients.
微生理系统 (MPS) 的目的是模拟动态的微环境和组织间的相互作用。虽然 MPS 已经被用于研究药物，但它们在化妆品成分方面的适用性尚未得到评估。HUMIMIC Chip2（"Chip2"）是第一个将皮肤模型纳入的多器官芯片技术，允许测试局部途径。因此，我们使用该模型分析了两种局部暴露的化学物质，贯叶金丝桃素和氯菊酯，不同暴露情景对它们药代动力学和药效学的影响。Chip2 纳入了重建的人类表皮模型（EpiDerm™）和 HepaRG 星状细胞球体。使用单个器官原代细胞的静态孵育进行的初步实验有助于确定最佳剂量。在 Chip2 研究中，在单次和重复局部或全身给药后 5 天内，分析了电路中的母体和代谢物。测量肝球体中相关外源代谢酶的基因表达，以反映化合物在肝脏中的毒代动力学效应。结果表明：1）EpiDerm™和肝球体的代谢能力在五天内得以维持；2）EpiDerm™模型的屏障功能保持完整；3）与单次应用相比，重复应用化合物会导致母体化合物和大多数代谢物的浓度更高；4）化合物特异性基因诱导，如贯叶金丝桃素诱导 CYP3A4，取决于应用途径和频率；5）不同的应用途径会影响实验过程中芯片中母体和代谢物的全身浓度；6）具有良好的实验室内和实验室间重现性。对于氯菊酯，可以模拟在人体内的排泄过程，这与体内情况非常相似。这些结果支持使用 Chip2 模型提供与局部应用化妆品成分的风险评估相关的母体和代谢物处置的信息。
