Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte‐based cell culture as <i>in vitro</i> alternatives for chemical testing: activating enzymes (Phase I)

Götz, Claudia; Pfeiffer, Roland; Tigges, Julia; Blatz, Veronika; Jäckh, Christine; Freytag, Eva-Maria; Fabian, Eric; Landsiedel, Robert; Merk, Hans F.; Krutmann, Jean; Edwards, Robert J.; Pease, Camilla; Goebel, Carsten; Hewitt, Nicola J.; Fritsche, Ellen

doi:10.1111/j.1600-0625.2012.01486.x

Cited by 103 publications

(79 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These low activities at a basal level are expected to limit the contribution of CYP metabolic pathway to overall dermal metabolism. This finding is in accordance with Götz et al, 53 who reported a very low basal activity in whole human skin. However, it has been shown that the activity of the enzymes can be considerably induced.…”

Section: Phase I Enzymessupporting

confidence: 83%

“…This is in contradiction with Janmohamed et al, 55 who reported mRNA expression of CYP2B6 in HaCat cells at an amount more similar to that in human skin compared with human keratinocytes. CYP3A basal enzyme activities were detected in HaCaT by Götz et al 53 but not by Rolsted et al 120 or by Janmohamed et al, 55 who failed to detect CYP3A4 mRNA. This discrepancy could be due to different HaCaT subclones.…”

Section: Primary Cells and Cell Linesmentioning

confidence: 93%

See 1 more Smart Citation

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

DumontCoralie

PrietoPilar

AsturiolDavid

et al. 2015

Applied In Vitro Toxicology

View full text Add to dashboard Cite

The exposure of the skin to consumer products, drugs, and environmental chemicals can result in their penetrating the skin barrier and entering systemic circulation, potentially resulting in adverse effects in the skin and other organs. The assessment of dermal penetration and bioavailability (including penetration, metabolism, and entry into the systemic circulation) is therefore an important consideration in the risk assessment of chemicals. The skin is a heterogeneous organ with a multilayer structure. Based on its architecture and physiology, substances can penetrate through three major ways but can also be blocked in the different skin layers and in the skin appendages, which act as reservoir. In addition to that, as the skin is a metabolically competent organ, substances can undergo metabolism. After a brief description of the skin architecture, this review will focus on the skin penetration mechanisms and skin metabolic capacities. The skin absorption has traditionally been tested in vivo on animals. However, with the new legislation (i.e., Registration, Evaluation, Authorisation, and Restriction of Chemicals Regulation or Cosmetics Regulation), alternatives to animal testing have to be implemented. In a second part, this review will provide a description of the main in vitro and in silico or computational models available to study skin absorption and skin metabolism (i.e., ex vivo skin models, artificial membrane barriers, primary cells and cell lines, Quantitative Structure-Activity Relationship [QSAR], simulators for the prediction of skin metabolism).

show abstract

Section: Phase I Enzymessupporting

confidence: 83%

Section: Primary Cells and Cell Linesmentioning

confidence: 93%

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

DumontCoralie

PrietoPilar

AsturiolDavid

et al. 2015

Applied In Vitro Toxicology

View full text Add to dashboard Cite

show abstract

“…It has been shown that cutaneous biotransformation can inactivate toxic agents; however, at the same time, biotransformation may also contribute to sensitization and genotoxicity. Comprehensive investigations into the expression and functionality of enzymes involved in cutaneous biotransformation of xenobiotics in human skin ex vivo as well as in reconstructed tissue models are ongoing, and knowledge continues to improve (Gotz et al, 2012;Huh et al, 2010;Oesch et al, 2014). Pre-validation studies have in fact been conducted with HSEs to address genotoxicity (Brinkmann et al, 2013;Fautz et al, 2013) and skin metabolism (Schafer-Korting et al, 2006).…”

Section: Tab 1: Models For Dermal Absorptionmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

View full text Add to dashboard Cite

SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

show abstract

“…The K m of carbazeran 4-hydroxylation with partially purified human AO was 40 mM (Beedham et al, 1987), whereas Dalvie et al (2010) reported a K m of 3.4 mM for zoniporide 2-hydroxylation in pooled human liver cytosol. Data from existing literature suggest that cutaneous phase II metabolic enzymes, for example, UGTs, SULTs, and NATs (Luu-The et al, 2009;Bonifas et al, 2010a,b;Hu et al, 2010;Jäckh et al, 2011;Kushida et al, 2011;Götz et al, 2012b;van Eijl et al, 2012), have higher expression and activity levels compared with corresponding cutaneous phase I metabolic enzymes (Jäckh et al, 2011;Götz et al, 2012a). To compare the cutaneous activity of AO with the known cutaneous phase II reactions, this study tested the glucuronidation and sulfation of triclosan (Moss et al, 2000) and N-acetylation of p-toluidine (Götz et al, 2012b), together with hydroxylations of carbazeran and zoniporide.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Oxidase Activity in Fresh Human Skin

et al. 2014

View full text Add to dashboard Cite

Human aldehyde oxidase (AO) is a molybdoflavoenzyme that commonly oxidizes azaheterocycles in therapeutic drugs. Although high metabolic clearance by AO resulted in several drug failures, existing in vitro-in vivo correlations are often poor and the extrahepatic role of AO practically unknown. This study investigated enzymatic activity of AO in fresh human skin, the largest organ of the body, frequently exposed to therapeutic drugs and xenobiotics. Fresh, full-thickness human skin was obtained from 13 individual donors and assayed with two specific AO substrates: carbazeran and zoniporide. Human skin explants from all donors metabolized carbazeran to 4-hydroxycarbazeran and zoniporide to 2-oxo-zoniporide. Average rates of carbazeran and zoniporide hydroxylations were 1.301 and 0.164 pmol×mg skin, resulting in 13 and 2% substrate turnover, respectively, after 24 hours of incubation with 10 mM substrate. Hydroxylation activities for the two substrates were significantly correlated (r 2 = 0.769), with interindividual variability ranging from 3-fold (zoniporide) to 6-fold (carbazeran). Inclusion of hydralazine, an irreversible inhibitor of AO, resulted in concentration-dependent decrease of hydroxylation activities, exceeding 90% inhibition of carbazeran 4-hydroxylation at 100 mM inhibitor. Reaction rates were linear up to 4 hours and well described by MichaelisMenten enzyme kinetics. Comparison of carbazeran and zoniporide hydroxylation with rates of triclosan glucuronidation and sulfation and p-toluidine N-acetylation showed that cutaneous AO activity is comparable to tested phase II metabolic reactions, indicating a significant role of AO in cutaneous drug metabolism. To our best knowledge, this is the first report of AO enzymatic activity in human skin.

show abstract

Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte‐based cell culture as in vitro alternatives for chemical testing: activating enzymes (Phase I)

Cited by 103 publications

References 66 publications

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Aldehyde Oxidase Activity in Fresh Human Skin

Contact Info

Product

Resources

About