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

Manevski, Nenad; Swart, Piet; Balavenkatraman, Kamal K.; Bertschi, Barbara; Camenisch, Gian; Kretz, Olivier; Schiller, Hilmar; Walles, Markus; Ling, Barbara; Wettstein, Reto; Schaefer, Dirk J.; Itin, Peter; Ashton‐Chess, Joanna; Pognan, François; Wolf, Armin; Litherland, Karine

doi:10.1124/dmd.114.060350

Cited by 44 publications

(43 citation statements)

References 65 publications

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“…It is known that phase II metabolism (conjugation) does occur in human skin [58]. In fact, the use of skin explants demonstrated full coverage for glucuronidation, sulfation, N -acetylation, catechol methylation and glutathione conjugation, and investigators and cosmetic companies have explored the applications of natural compound analogs to address this issue [57,58,59].…”

Section: Human Skin Gene Expressionmentioning

confidence: 99%

“…In fact, the use of skin explants demonstrated full coverage for glucuronidation, sulfation, N -acetylation, catechol methylation and glutathione conjugation, and investigators and cosmetic companies have explored the applications of natural compound analogs to address this issue [57,58,59]. However, the conjugation enzymatic activities in human skin are in the pmol/mg skin/h range.…”

Section: Human Skin Gene Expressionmentioning

confidence: 99%

“…However, the conjugation enzymatic activities in human skin are in the pmol/mg skin/h range. As noted by Manevski et al “comparison of the skin and liver organ clearances implies that the skin contributes only marginally to the total systemic phase II enzyme-mediated metabolic elimination in humans” [58]. …”

Section: Human Skin Gene Expressionmentioning

confidence: 99%

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Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

Lephart

2017

IJMS

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Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4′ acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4′ analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin.

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Section: Human Skin Gene Expressionmentioning

confidence: 99%

Section: Human Skin Gene Expressionmentioning

confidence: 99%

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Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

Lephart

2017

IJMS

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“…Recently Manevski et al (2015) reported for human skin N-acetylation for the first time for procainamide as substrate. Of totally 11 substrates for 5 xenobiotic conjugating enzyme activities the highest observed activity was N-acetylation of para-toluidine.…”

Section: Introductionmentioning

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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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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“…SIRT1: NAD-dependent deacetylase sirtuin-1 or silent mating type information regulation 2 homolog 1; TIMP1: tissue inhibitor of the matrix metalloproteinase 1; MMPs: matrix metalloproteinases significant extent since this enzymatic activity only operates in the picomole range compared to the liver that has very high conjugation levels, which has been discussed elsewhere. 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.…”

Section: Discussionmentioning

confidence: 99%

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

Cited by 44 publications

References 65 publications

Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

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

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

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