Percutaneous penetration of typical Organophosphate esters under catalysis by Carboxylesterase: Characteristics, mechanism and prediction model

IF 10.3 1区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
Yan Yang , Yuwan Hou , Yonglong Liao , Zeji Huang , Jiejie Pan , Xin Yang , Haojia Chen , Zenghua Qi
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Abstract

Although the relationship between organophosphate esters (OPEs) percutaneous penetration and their specific physicochemical properties has been investigated, little information is available regarding the percutaneous penetration of OPEs under the interaction of skin enzymes. Herein, we used an in vitro skin model to quantitatively assess the skin permeation of six typical OPEs. The in vitro results demonstrated that 0.34–49.87% of OPEs and 0.80–2.95% of their metabolites (mOPEs) penetrated the skin. Notably, triphenyl phosphate (TPHP) and tri-3-cresyl phosphate (TCRP), which exhibit high lipophilicity and large molecular weights, were more likely to be deposited in the skin tissue, thereby hindering their penetration into the body. However, the concentrations of their metabolites, diphenyl hydrogen phosphate (DPHP) and bis(2-methylphenoxy) phosphinic acid (DCRP), in the receptor fluid were approximately six times higher than those of their parent compounds. After in vivo dermal OPE exposure, all parent OPEs were detected in both the stratum corneum and viable tissue (VT). Proteomic analysis and enzymatic hydrolysis experiments revealed that the percutaneous biotransformation of OPEs in VT is mediated primarily by carboxylesterase (CES). A biomimetic bilayer skin membrane based on the CES level in fresh skin yielded results closer to the real skin absorption data of OPEs than prior models. Thus, a more accurate prediction model was established to assess the percutaneous penetration of OPEs. Our results provide valuable insights into the skin absorption of OPEs and emphasize the role of skin CES in calculating and predicting the percutaneous penetration of OPEs.

Abstract Image

Abstract Image

虽然已经对有机磷酸酯(OPEs)的经皮渗透性与其特定理化性质之间的关系进行了研究,但有关 OPEs 在皮肤酶作用下的经皮渗透性的信息却很少。在此,我们利用体外皮肤模型对六种典型 OPE 的皮肤渗透性进行了定量评估。体外实验结果表明,0.34-49.87% 的 OPE 和 0.80-2.95% 的代谢物(mOPEs)可渗透皮肤。值得注意的是,磷酸三苯酯(TPHP)和磷酸三-3-甲酚酯(TCRP)具有较高的亲脂性和较大的分子量,更有可能沉积在皮肤组织中,从而阻碍其渗入人体。不过,它们的代谢物磷酸二苯基氢(DPHP)和双(2-甲基苯氧基)膦酸(DCRP)在受体液中的浓度大约是其母体化合物浓度的六倍。体内皮肤接触 OPE 后,在角质层和有活力组织(VT)中都检测到了所有母体 OPE。蛋白质组分析和酶水解实验表明,OPE 在 VT 中的经皮生物转化主要是由羧基酯酶(CES)介导的。基于新鲜皮肤中 CES 水平的生物仿真双层皮肤膜得出的结果比之前的模型更接近 OPE 的真实皮肤吸收数据。因此,我们建立了一个更准确的预测模型来评估 OPE 的经皮渗透性。我们的研究结果为了解 OPE 的皮肤吸收情况提供了有价值的见解,并强调了皮肤 CES 在计算和预测 OPE 经皮渗透中的作用。
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来源期刊
Environment International
Environment International 环境科学-环境科学
CiteScore
21.90
自引率
3.40%
发文量
734
审稿时长
2.8 months
期刊介绍: Environmental Health publishes manuscripts focusing on critical aspects of environmental and occupational medicine, including studies in toxicology and epidemiology, to illuminate the human health implications of exposure to environmental hazards. The journal adopts an open-access model and practices open peer review. It caters to scientists and practitioners across all environmental science domains, directly or indirectly impacting human health and well-being. With a commitment to enhancing the prevention of environmentally-related health risks, Environmental Health serves as a public health journal for the community and scientists engaged in matters of public health significance concerning the environment.
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