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Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

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Author: Gibbs, S. · Sandt, J.J.M. van de · Merk, H.F. · Lockley, D.J. · Pendlington, R.U. · Pease, C.K.
Institution: TNO Kwaliteit van Leven
Source:Current Drug Metabolism, 8, 8, 758-772
Identifier: 240329
doi: doi:10.2174/138920007782798225
Keywords: Biology · 3D skin reconstructs · Cytochrome P450 · IDO expression · In vitro skin absorption · Microarray · Peptidases · 1 chloro 2,4 dinitrobenzene · 2 nitro 1,4 phenylenediamine · 4 aminophenol · alcohol dehydrogenase · aldehyde dehydrogenase · alpha tocopherol · atrazine · azo reductase · carnitine · cinnamaldehyde · cinnamyl alcohol · clobetasol propionate · cytochrome P450 · esterase · hydrogen peroxide · messenger RNA · nicotinic acid ethyl ester · oxygenase · phenylenediamine · propoxur · propranolol · resorufin · retinoic acid · retinol palmitate · T 2 toxin · toxic substance · triclosan · triolein · unindexed drug · xenobiotic agent · biotransformation · chemical carcinogenesis · environmental exposure · enzyme assay · ex vivo study · human · immunohistochemistry · in vitro study · nonhuman · Northern blotting · occupational exposure · protein expression · protein function · review · skin absorption · skin allergy · skin cancer · skin carcinogenesis · skin inflammation · skin sensitization · skin toxicity · toxicokinetics · Western blotting · xenobiotic metabolism · Biotransformation · Humans · Models, Biological · Skin · Xenobiotics


In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental chemical exposure, it is also a potential target organ for adverse health effects. Occupational, accidental or intended-use exposure to toxic chemicals could result in acute or delayed injury to the skin (e.g. inflammation, allergy, cancer). Skin metabolism may play a role in the manifestation or amelioration of adverse effects via the topical route. Today, we have robust testing strategies to assess the potential for local skin toxicity of chemical exposure. Such methods (e.g. the local lymph node assay for assessing skin sensitisation; skin painting carcinogenicity studies) incorporate skin metabolism implicitly in the in vivo model system used. In light of recent European legislation (i.e. 7th Amendment to the Cosmetics Directive and Registration Evaluation and Authorisation of existing Chemicals (REACH)), non-animal approaches will be required to reduce and replace animal experiments for chemical risk assessment. It is expected that new models and approaches will need to account for skin metabolism explicitly, as the mechanisms of adverse effects in the skin are deconvoluted. 3D skin models have been proposed as a tool to use in new in vitro alternative approaches. In order to be able to use 3D skin models in this context, we need to understand their metabolic competency in relation to xenobiotic biotransformation and whether functional activity is representative of that seen in human skin. © 2007 Bentham Science Publishers Ltd.