Nicola J Hewitt, Manuela Mayer, Andreas Schepky, Corie Ellison
{"title":"用Caco-2测定16种直链和支链对羟基苯甲酸酯的渗透性。","authors":"Nicola J Hewitt, Manuela Mayer, Andreas Schepky, Corie Ellison","doi":"10.1002/jat.4917","DOIUrl":null,"url":null,"abstract":"<p><p>The in vitro intestinal permeability of straight- and branched-chain parabens has not been extensively investigated. Sixteen parabens were tested in the Caco-2 assay. Passive diffusion was measured using PAMPA. The transport of the MCT1 substrate, p-coumaric acid, as well as propylparaben and isopropylparaben, was investigated. For straight-chain parabens, P<sub>app A-B</sub> and P<sub>app B-A</sub> decreased with increasing chain length and LogP. P<sub>app B-A</sub> values were similar to PAMPA permeability (P<sub>app PAMPA</sub>), indicating passive diffusion. Losses in mass balance were due to non-specific binding, accumulation in the cells, and/or hydrolysis to 4-hydroxybenzoic acid (4-HBA). The extent of hydrolysis of straight-chain parabens was inversely proportional to their LogP, suggesting they are carboxylesterase-1 (CES1) substrates. For C1-C5 straight-chain parabens, P<sub>app A-B</sub> was higher than P<sub>app B-A</sub>, indicating vectoral permeability. Transport of parent propylparaben was passive and pH-independent, but 4-HBA formed was actively transported out of the cells, which was pH-dependent. This indicated the involvement of apical MCT1 transporters (their presence was confirmed using p-coumaric acid). Kinetics measurements suggested that efflux of 4-HBA is predominantly via the basolateral membrane. Branched-chain parabens with good passive diffusion were poor CES1 substrates but may be transported via processes other than 4-HBA MCT1 efflux. In conclusion, P<sub>app</sub> values for parabens are best calculated using parent chemical and 4-HBA. The extent of vectoral permeability of straight-chain but not branched-chain parabens is correlated to the extent of hydrolysis and the concentration-dependent contribution of passive vs. active efflux of parent and 4-HBA, respectively.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Permeability of 16 Straight- and Branched-Chain Parabens Using the Caco-2 Assay.\",\"authors\":\"Nicola J Hewitt, Manuela Mayer, Andreas Schepky, Corie Ellison\",\"doi\":\"10.1002/jat.4917\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The in vitro intestinal permeability of straight- and branched-chain parabens has not been extensively investigated. Sixteen parabens were tested in the Caco-2 assay. Passive diffusion was measured using PAMPA. The transport of the MCT1 substrate, p-coumaric acid, as well as propylparaben and isopropylparaben, was investigated. For straight-chain parabens, P<sub>app A-B</sub> and P<sub>app B-A</sub> decreased with increasing chain length and LogP. P<sub>app B-A</sub> values were similar to PAMPA permeability (P<sub>app PAMPA</sub>), indicating passive diffusion. Losses in mass balance were due to non-specific binding, accumulation in the cells, and/or hydrolysis to 4-hydroxybenzoic acid (4-HBA). The extent of hydrolysis of straight-chain parabens was inversely proportional to their LogP, suggesting they are carboxylesterase-1 (CES1) substrates. For C1-C5 straight-chain parabens, P<sub>app A-B</sub> was higher than P<sub>app B-A</sub>, indicating vectoral permeability. Transport of parent propylparaben was passive and pH-independent, but 4-HBA formed was actively transported out of the cells, which was pH-dependent. This indicated the involvement of apical MCT1 transporters (their presence was confirmed using p-coumaric acid). Kinetics measurements suggested that efflux of 4-HBA is predominantly via the basolateral membrane. Branched-chain parabens with good passive diffusion were poor CES1 substrates but may be transported via processes other than 4-HBA MCT1 efflux. In conclusion, P<sub>app</sub> values for parabens are best calculated using parent chemical and 4-HBA. The extent of vectoral permeability of straight-chain but not branched-chain parabens is correlated to the extent of hydrolysis and the concentration-dependent contribution of passive vs. active efflux of parent and 4-HBA, respectively.</p>\",\"PeriodicalId\":15242,\"journal\":{\"name\":\"Journal of Applied Toxicology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Applied Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/jat.4917\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Applied Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jat.4917","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}
Permeability of 16 Straight- and Branched-Chain Parabens Using the Caco-2 Assay.
The in vitro intestinal permeability of straight- and branched-chain parabens has not been extensively investigated. Sixteen parabens were tested in the Caco-2 assay. Passive diffusion was measured using PAMPA. The transport of the MCT1 substrate, p-coumaric acid, as well as propylparaben and isopropylparaben, was investigated. For straight-chain parabens, Papp A-B and Papp B-A decreased with increasing chain length and LogP. Papp B-A values were similar to PAMPA permeability (Papp PAMPA), indicating passive diffusion. Losses in mass balance were due to non-specific binding, accumulation in the cells, and/or hydrolysis to 4-hydroxybenzoic acid (4-HBA). The extent of hydrolysis of straight-chain parabens was inversely proportional to their LogP, suggesting they are carboxylesterase-1 (CES1) substrates. For C1-C5 straight-chain parabens, Papp A-B was higher than Papp B-A, indicating vectoral permeability. Transport of parent propylparaben was passive and pH-independent, but 4-HBA formed was actively transported out of the cells, which was pH-dependent. This indicated the involvement of apical MCT1 transporters (their presence was confirmed using p-coumaric acid). Kinetics measurements suggested that efflux of 4-HBA is predominantly via the basolateral membrane. Branched-chain parabens with good passive diffusion were poor CES1 substrates but may be transported via processes other than 4-HBA MCT1 efflux. In conclusion, Papp values for parabens are best calculated using parent chemical and 4-HBA. The extent of vectoral permeability of straight-chain but not branched-chain parabens is correlated to the extent of hydrolysis and the concentration-dependent contribution of passive vs. active efflux of parent and 4-HBA, respectively.
期刊介绍：
Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
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