Metabolism of 3-lndolylacetic Acid during Percutaneous Absorption in Human Skin

Ademola, John I.; Wester, Ronald C.; Maibach, Howard I.

doi:10.1002/jps.2600820207

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…7). Even if some previous studies reported activities in microsomes prepared from frozen (Gotz et al, 2012) or cadaver human skin (Ademola et al, 1993), the results presented here suggest that using fresh human skin is of high importance for drug metabolism studies. If the frozen full-thickness skin samples are used as an alternative to fresh tissue, further studies are needed to define the optimal and fully controlled freezing conditions, similar to ongoing efforts in preparing cryopreserved liver and kidney tissue slices [Fahy et al (2013) and references therein].…”

Section: Discussioncontrasting

confidence: 42%

“…Use of three-dimensional reconstructed skin models and immortalized cell lines (e.g., HaCaT cells) raises concerns of altered gene expression, even if existing studies are mostly encouraging (Bonifas et al, 2010b;Jackh et al, 2011;Gotz et al, 2012). 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.…”

Section: Introductionmentioning

confidence: 99%

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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

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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Section: Discussioncontrasting

confidence: 42%

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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“…Reports on UGT enzyme activity mostly refer to liver, while activity data on skin UGT are rare. However, reports on indolylacetic acid glucuronides and generation of triclosan glucuronides demonstrate the presence of UGT activity in skin (42,43). Our results support these findings by measuring 4‐MU:UGT activity in microsomal preparations from human ex vivo skin.…”

Section: Discussionmentioning

confidence: 99%

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: phase II enzymes

Götz

Pfeiffer

Tigges

et al. 2012

Experimental Dermatology

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The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first‐pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals. Thus, there is an urgent need to understand the xenobiotic‐metabolizing capacities of human skin and to compare these activities to models developed to replace animal testing. We have measured the activity of the phase II enzymes glutathione S‐transferase, UDP‐glucuronosyltransferase and N‐acetyltransferase in ex vivo human skin, the 3D epidermal model EpiDerm 200 (EPI‐200), immortalized keratinocyte‐based cell lines (HaCaT and NCTC 2544) and primary normal human epidermal keratinocytes. We show that all three phase II enzymes are present and highly active in skin as compared to phase I. Human skin, therefore, represents a more detoxifying than activating organ. This work systematically compares the activities of three important phase II enzymes in four different in vitro models directly to human skin. We conclude from our studies that 3D epidermal models, like the EPI‐200 employed here, are superior over monolayer cultures in mimicking human skin xenobiotic metabolism and thus better suited for dermatotoxicity testing.

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“…Numerous health and household products contain chemicals metabolized by human skin such as triclosan, which undergoes both glucuronidation and sulfation (Moss et al, 2000). The indole glucuronide metabolite of indolylacetic acid was detected in human skin samples (Ademola et al, 1993). NATs are expressed in human skin, and they are important in the detoxification of certain cosmetic chemicals such as hair dyes that contain aromatic amines.…”

Section: Phase II Metabolic Enzymesmentioning

confidence: 99%

Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions

Sharma¹,

Uetrecht²

2013

Drug Metabolism Reviews

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Drug-induced skin rashes are poorly understood idiosyncratic reactions, and current methods cannot predict their occurrence. Most idiosyncratic drug reactions are thought to be caused by chemically reactive metabolites, and the skin is a frequent site of idiosyncratic reactions; however, the skin has a very limited capacity to metabolize drugs. To balance this, the skin represents a protective barrier with a very active immune response against pathogens and other types of skin injury. Therefore its response to reactive metabolites is quite different from that of the liver. The purpose of this review is to integrate emerging findings into proposed mechanisms of drug and carcinogen metabolism in the skin that are likely responsible for rashes and other immune responses of the skin. Current evidence suggests the skin possesses significant sulfotransferase and flavin monooxygenases activities, but very low cytochromes P450 activity. However, there are skin-specific P450s that are not present in the liver. The manner in which the skin responds to neoantigens through local antigen presentation and innate immune sensing is reviewed with a focus on insights gained from the contact hypersensitivity (CHS) field. The roles of keratinocytes and Langerhans cells, and the emerging function of NOD-like receptors, are highlighted.

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Metabolism of 3-lndolylacetic Acid during Percutaneous Absorption in Human Skin

Cited by 8 publications

References 20 publications

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

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

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: phase II enzymes

Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions

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