Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes  in vitro

Manwaring, John; Rothe, Helga; Obringer, Cindy; Foltz, David J.; Baker, Timothy R.; Troutman, John; Hewitt, Nicola J.; Goebel, Carsten

doi:10.1016/j.taap.2015.05.016

Cited by 20 publications

(13 citation statements)

References 25 publications

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“…With respect to N-acetyltransferase enzymatic activity recently Manwaring et al (2015) reported N-acetylation as the major pathway of metabolism in human skin ex vivo for several aromatic amine hair dyes. Thus, after 60 min exposure to 1.5 mg/cm 2 skin in receptor fluid collected for 24 h the percentage of acetylated metabolite was 86% for 4-amino-2-hydroxytoluene and 72% for 4-amino- m -cresol, after 60 min exposure to 1.0 mg/cm 2 skin 85% for 2-amino-5-ethylphenol, after 60 min exposure to 2.22 mg/cm 2 skin 90% for toluene-2,5-diamine.…”

Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

“…Of totally 11 substrates for five xenobiotic-metabolizing enzyme activities (glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation) the highest observed activity in human skin (fresh whole skin explants) was N-acetylation of para-toluidine (4.76 pmol/mg skin/h) (Manevski et al 2015). Recently Manwaring et al (2015) reported N-acetylation as the major pathway of metabolism in the human keratinocytic cell line HaCaT for several aromatic amine hair dyes. Thus, after 24 h incubation of 0.625 µg/mL in the medium the percentage of acetylated metabolite was 79% for 4-amino-2-hydroxytoluene, after 24 h incubation of 0.492 µg/mL 100% for 4-amino- m -cresol, after 24 h incubation of 0.5 µg/mL 100% for 2-amino-5-ethylphenol, after 24 h incubation of 0.35 µg/mL 100% for toluene-2,5-diamine and after 24 h incubation of 0.59 µg/mL 100% for p -phenylenediamine.…”

Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

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Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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“…The liver is the principal organ responsible for metabolism following absorption of a substance and its arrival in blood circulation. Isolated hepatocytes were thus used as it has been demonstrated that appropriate toxicokinetic information can be generated based solely on in vitro data, with the resulting data being in the same order of magnitude as those published for human volunteers [61].…”

Section: Toxicokinetic Studiesmentioning

confidence: 99%

Alternative Methods to Animal Testing for the Safety Evaluation of Cosmetic Ingredients: An Overview

Vinardell

Mitjans

2017

Cosmetics

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Abstract:The safety of cosmetics sold in Europe is based on the safety evaluation of each individual ingredient conducted by those responsible for putting the product on the market. However, those substances for which some concern exists with respect to human health (e.g., colorants, preservatives, UV-filters, nanomaterials) are evaluated at the European Commission level by a scientific committee, currently called the Scientific Committee on Consumer Safety (SCCS). According to the Cosmetics Regulation (European Commission, 2009), it is prohibited in the European Union (EU) to market cosmetic products and ingredients that have been tested on animals. However, the results of studies performed before the ban continue to be accepted. In the current study, we evaluated the use of in vitro methods in the dossiers submitted to the SCCS in the period between 2013 and 2016 based on the published reports issued by the scientific committee, which provides a scientific opinion on these dossiers. The results of this evaluation were compared with those of an evaluation conducted four years previously. We found that, despite a slight increase in the number of studies performed in vitro, the majority of studies submitted to the SCCS is still done principally in vivo and correspond to studies performed before the ban.

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“…There are several skin models that can be used to investigate the metabolism of chemicals including: keratinocytes (Manwaring et al, 2015), skin (Hewitt, Perkins, & Hotchkiss, 2000), reconstructed human epidermal (RHE) models (Bacqueville et al, 2017;Eilstein et al, 2014;Eilstein et al, 2015;Luu-The et al, 2007;Luu-The et al, 2009), and skin explants (Genies et al, 2018;Jacques et al, 2014). In the present study, we have used the S9 subcellular fractions of the RHE model, EpiSkin™ (EPISKIN SA, Lyon, France), in a screening assay to provide an indication of the metabolic stability of chemicals in the skin.…”

Section: Introductionmentioning

confidence: 99%

Use of human liver and EpiSkin™ S9 subcellular fractions as a screening assays to compare the in vitro hepatic and dermal metabolism of 47 cosmetics‐relevant chemicals

Eilstein

Grégoire

Fabre

et al. 2020

J of Applied Toxicology

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The abundance of xenobiotic metabolizing enzymes (XMEs) is different in the skin and liver; therefore, it is important to differentiate between liver and skin metabolism when applying the information to safety assessment of topically applied ingredients in cosmetics. Here, we have employed EpiSkin™ S9 and human liver S9 to investigate the organ‐specific metabolic stability of 47 cosmetic‐relevant chemicals. The rank order of the metabolic rate of six chemicals in primary human hepatocytes and liver S9 matched relatively well. XME pathways in liver S9 were also present in EpiSkin S9; however, the rate of metabolism tended to be lower in the latter. It was possible to rank chemicals into low‐, medium‐ and high‐clearance chemicals and compare rates of metabolism across chemicals with similar structures. The determination of the half‐life for 21 chemicals was affected by one or more factors such as spontaneous reaction with cofactors or non‐specific binding, but these technical issues could be accounted for in most cases. There were seven chemicals that were metabolized by liver S9 but not by EpiSkin S9: 4‐amino‐3‐nitrophenol, resorcinol, cinnamyl alcohol and 2‐acetylaminofluorene (slowly metabolized); and cyclophosphamide, benzophenone, and 6‐methylcoumarin. These data support the use of human liver and EpiSkin S9 as screening assays to indicate the liver and skin metabolic stability of a chemical and to allow for comparisons across structurally similar chemicals. Moreover, these data can be used to estimate the systemic bioavailability and clearance of chemicals applied topically, which will ultimately help with the safety assessment of cosmetics ingredients.

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Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro

Cited by 20 publications

References 25 publications

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

Alternative Methods to Animal Testing for the Safety Evaluation of Cosmetic Ingredients: An Overview

Use of human liver and EpiSkin™ S9 subcellular fractions as a screening assays to compare the in vitro hepatic and dermal metabolism of 47 cosmetics‐relevant chemicals

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