Xenobiotic Metabolism in Human Skin and 3D Human Skin Reconstructs: A Review

Abstract

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. 7(th) 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.

Cutaneous Metabolism in Transdermal Drug Delivery

“…Nohynek et al [40] used a commercially available reconstructed human epidermis for the safety assessment of the oxidative arylamine hair dye ingredients para-aminophenol and para-phenylenediamine. Recently, by comparing xenobiotic metabolism studies both in human skin and 3D human skin reconstructs, Gibbs et al [41] suggested that skin reconstructs could became a fully defined in vitro model for investigating enzymemediated xenobiotic metabolism in the skin, and a potential alternative to animal models. However, a key issue, especially for transformed keratinocyte cell lines and 3D cell cultures, is if enzymatic patterns can be fully expressed as in vivo original cells.…”

“…For example, bovine serum albumin (BSA), commonly used in receptor media in permeation studies to increase solubility of lipophilic substances, was found strongly inhibiting the metabolism of topically applied prednicarbate in reconstructed epidermis [48]. Moreover, the 6-well plate system was introduced for maintaining skin viability under optimal conditions during culture in a humidified incubator [41,49].…”

Chemical reactivity indices and mechanism‐based read‐across for non‐animal based assessment of skin sensitisation potential

“…Ideally an experimental method for identifying potentially sensitising pro-electrophiles would include appropriate metabolic and abiotic activating capability reflective of that in skin. However, so little is known about skin metabolism to date (recently reviewed in Gibbs et al, 2007), that finding a suitable metabolising system could present a significant challenge in assay development.…”

From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment

“…Depending on lipophilicity and molecular weight, the rate and route of transport across stratum corneum varies, predominating through either the lipid bilayers, corneocytes or via appendages such as sweat ducts and hair follicles (Potts and Guy, 1992;Mitragotri, 2003;Magnusson et al, 2004). Once present in the viable skin, the ingredient will distribute between extra-and intra-cellular space, where there is the potential for both phase I (activation of pro-haptens) and phase II (predominantly clearing) metabolism (Gibbs et al, 2007;Hagvall et al, 2008;van Eijl et al, 2012). Finally, the ingredient is cleared from the viable skin via the dermal capillary bed.…”