Xenobiotic metabolism gene expression in the EpiDerm™ in vitro 3D human epidermis model compared to human skin

Hu, Ting; Khambatta, Zubin S.; Hayden, Patrick; Bolmarcich, Jennifer; Binder, Robert L.; Robinson, Michael K.; Carr, Gregory J.; Tiesman, Jay P.; Jarrold, Bradley B.; Osborne, Rosemarie; Reichling, Tim; Nemeth, Suzanne; Aardema, Marilyn J.

doi:10.1016/j.tiv.2010.03.013

Cited by 95 publications

(83 citation statements)

References 68 publications

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“…During simulation, cells build up the characteristic triangular structure of the EET, The basis of our study is formed by commercially available, organotypic skin cultures, developed and manufactured in a good manufacturing practice-approved process. In many publications regarding different molecular and morphological readouts, they have shown a biological response equivalent to human skin (Hayden et al, 2009) comprising cytokine secretion (Mallampati et al, 2010) as well as proliferative (Black et al, 2010), inflammatory, and metabolic markers (Hu et al, 2010). To further provide evidence of the in vivo relevance of our wound model, we measured the temporal profile of key cytokines regulating cell behavior and compared it with previously published clinical skin-wounding data.…”

Section: Computational Modeling Leads To the Esmmentioning

confidence: 99%

Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Safferling¹,

Sütterlin²,

Westphal³

et al. 2013

J Exp Med

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Section: Computational Modeling Leads To the Esmmentioning

confidence: 99%

Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Safferling¹,

Sütterlin²,

Westphal³

et al. 2013

J Exp Med

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“…This study focused on activities of cutaneous phase II metabolic enzymes. A literature survey suggested that mRNA expression of phase II metabolic enzymes is higher than expression of corresponding phase I enzymes in human skin (Luu-The et al, 2009;Hu et al, 2010;van Eijl et al, 2012). Numerous detected cutaneous transferases (Table 1), namely UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs), catechol-O-methyltransferase (COMT), and glutathione-S-transferases (GSTs), indicate a potentially significant role of the human skin in metabolic elimination and detoxification.…”

Section: Introductionmentioning

confidence: 99%

“…Skin explants were rarely used in the past and mostly dermatomed to thickness below 500 mm (Ademola et al, 1993;Moss et al, 2000;Goebel et al, 2009;Zalko et al, 2011), thus minimizing the potential metabolic contributions of skin dermis. Taken together, difficulties in accessing fresh human tissue, lack of alternative and simpler model validation against the full-thickness human skin, limited selection of test substrates, and potential enzyme inactivation in skin subcellular Blacker et al, 1991;Raza et al, 1991;Luu-The et al, 2009;Hu et al, 2010;van Eijl et al, 2012 a Enzymes with higher reported expression. fractions all contribute to limited knowledge about phase II metabolism in the human skin.…”

Section: Introductionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17b-estradiol, N-acetylprocainamide, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 mM substrate incubations spanned a 1000-fold: from the highest 4.758 pmol·mg skin ·h -1 for 17b-estradiol 17-glucuronidation. Interindividual variability was 1.4-to 13.0-fold, the highest being 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 hours, although 24-hour incubations enabled detection of metabolites in trace amounts. All reactions were unaffected by the inclusion of cosubstrates, and freezing of the fresh skin led to loss of glucuronidation activity. The predicted whole-skin intrinsic metabolic clearances were significantly lower compared with corresponding whole-liver intrinsic clearances, suggesting a relatively limited contribution of the skin to the body's total systemic phase II enzymemediated metabolic clearance. Nevertheless, the fresh full-thickness skin explants represent a suitable model to study cutaneous phase II metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role in skin adverse reactions.

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“…18,39 It should be noted that phase I metabolism has been reported in intact human skin samples and comparisons have been made to in vitro skin models where, in general, the degree or levels of cytochrome 450 (CYP) and esterase activity are similar among the human epidermal/dermal layers and the 3D human skin models with epidermal components. [40][41][42][43] It is not known whether esterase activity via phase I metabolism played a role in the outcomes of the present study. However, phase II metabolism in intact skin and in in vitro skin models, in general, possess much lower conjugation and monooxygenation (via P450s) compared to liver tissue.…”

Section: Discussionmentioning

confidence: 85%

Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications

Lephart

Andrus

2017

Exp Biol Med (Maywood)

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Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.

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Xenobiotic metabolism gene expression in the EpiDerm™ in vitro 3D human epidermis model compared to human skin

Cited by 95 publications

References 68 publications

Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications

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