INRA, UMR 1089 Xénobiotiques, 180 Chemin de Tournefeuille, BP 93173, 31027 Toulouse Cedex 3, France.
Toxicol Lett. 2010 Nov 10;199(1):22-33. doi: 10.1016/j.toxlet.2010.08.001. Epub 2010 Aug 7.
Biotransformation of chemicals by the skin is a critical determinant of systemic exposure in humans following dermal absorption. Pig ear skin potentially represents a valuable alternative model since it closely resembles to human skin. We developed an ex vivo pig ear skin system which absorption, diffusion and metabolic capabilities were investigated using benzo(a)pyrene [B(a)P] as a model molecule. The potential of the ex vivo pig ear skin model to biotransform xenobiotics was compared with metabolic data obtained using dermal and hepatic microsomes from human and pig. (14)C-B(a)P [50-800 nmol] was applied on the surface of skin models. The diffusion and the production of B(a)P metabolites were quantified by radio-HPLC, LC-MS/MS and NMR. B(a)P was extensively metabolized by pig ear skin explants, the major metabolites being B(a)P-glucuronide and sulfate conjugates. B(a)P-OHs, B(a)P-diols, B(a)P-catechols and B(a)P-diones were also identified. In the pig ear skin model developed, skin diffusion was maintained over 72 h and both phase I and phase II activities were expressed, with the formation of similar metabolites as produced in incubations with liver and skin microsomal fractions. This ex vivo model, which combines a functional skin barrier and active biotransformation capabilities, appears to represent a valuable alternative tool in transdermal exposure studies.
皮肤对化学物质的生物转化是人体经皮吸收后系统暴露的关键决定因素。猪耳皮肤可能是一种有价值的替代模型，因为它与人皮肤非常相似。我们开发了一种离体猪耳皮肤系统，使用苯并[a]芘（B[a]P）作为模型分子，研究了其吸收、扩散和代谢能力。离体猪耳皮肤模型对外源化学物质的生物转化能力与用人和猪的皮肤和肝微粒体获得的代谢数据进行了比较。（14）C-B[a]P[50-800nmol]施用于皮肤模型表面。通过放射性 HPLC、LC-MS/MS 和 NMR 定量测定 B[a]P 代谢物的扩散和产生。B[a]P 被猪耳皮肤外植体广泛代谢，主要代谢产物为 B[a]P-葡糖苷酸和硫酸盐缀合物。还鉴定了 B[a]P-OHs、B[a]P-二醇、B[a]P-儿茶酚和 B[a]P-二酮。在开发的离体猪耳皮肤模型中，皮肤扩散在 72 小时内保持不变，并且表达了 I 相和 II 相活性，形成了与肝和皮肤微粒体部分孵育产生的类似代谢物。这种离体模型结合了功能皮肤屏障和活跃的生物转化能力，似乎是一种有价值的经皮暴露研究替代工具。
