Expression of Multiple Cytochrome P450 Enzymes and Multidrug Resistance-Associated Transport Proteins in Human Skin Keratinocytes

Baron, Jens Malte; Höller, Daniela; Schiffer, Ruth; Frankenberg, Silke; Neis, Mark M.; Merk, Hans F.; Jugert, Frank K.

doi:10.1046/j.1523-1747.2001.01298.x

Cited by 211 publications

(230 citation statements)

References 41 publications

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“…Early studies demonstrating the ability of animal skin to metabolize benzo[a]pyrene suggested expression of CYP1A1 in skin. Indeed, CYP1A1 mRNA has been found in all human skin sources probed to date, although data supporting expression of CYP1A1 protein is limited to KCs (Baron et al, 2001;Saeki et al, 2002;Yengi et al, 2003). In contrast, studies probing for CYP1A2 mRNA have found that message for expression of this gene in skin or skin cells is undetectable (Baron et al, 2001;Saeki et al, 2002).…”

Section: Evidence For the Expression Of Drug-metabolizing Enzymes In mentioning

confidence: 99%

Biotransformation of Drugs in Human Skin

Svensson

2008

Drug Metab Dispos

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ABSTRACT:Although it is the largest organ of the human body, skin is often not considered in discussions of drug metabolism. However, there is growing evidence that most common drug-metabolizing enzymes are expressed in the skin. Evidence for expression of cytochromes P450, flavin monooxygenases, glutathione-S-transferases, N-acetyltransferases, and sulfotransferases in human skin and skin cells are presented. Additional discussion is focused on the evidence of actual metabolism of drugs. Finally, the potential clinical implications of metabolism within the skin are discussed briefly.Representing the largest organ in the human body, skin provides an important barrier role in protecting the body from external chemicals and pathogens that would otherwise impair critical functions needed for survival. Comprised of a complex cellular network, skin is capable of many metabolic functions common to visceral organs, including the biotransformation of drugs that penetrate through its most external layer. In addition to being an important target for pharmacotherapy, delivery through the skin is increasingly used as an effective means of delivering drugs to the systemic circulation. It is also evident that biotransformation within the skin may be an essential step to manifesting cutaneous toxicity to certain drugs and chemicals. Hence, an understanding of the capacity and impact of drug biotransformation within skin is an important component in assessing pharmacotherapy directed to or through the cutaneous environment. In the present article, discussion will be limited to evidence for biotransformation of drugs generated specifically in human skin or skin cells. Although many investigations have probed the ability of skin from numerous species to metabolize a variety of environmental chemicals, the focus of the present review is on evidence for metabolism of therapeutic agents. The reader is referred to the recent review of Oesch et al. (2007) for a comparison of xenobiotic-metabolizing enzymes in the skin of various species. Overview of the Structure and Function of SkinExisting as a dynamic and flexible barrier, human skin serves a multifaceted role as the organ with the greatest exposure to the external environment. In addition to providing the primary means for tactile evaluation of the immediate surroundings, skin serves a critical role in thermoregulation of the body. The plethora of infectious diseases with cutaneous manifestations attests to the important sentinel role of skin in protecting the body from bacterial, fungal, and viral pathogens. Although this diversity of function is recognized, it is not surprising that skin is populated by numerous types of specialized cells (see Table 1) that enable dynamic interaction with the internal and external environment. Because studies assessing the role of skin in drug metabolism often use model cells, it is important to begin this review with a brief discussion of skin structure and function.Three identifiable layers comprise human skin: epidermis, dermis, and hypodermi...

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Section: Evidence For the Expression Of Drug-metabolizing Enzymes In mentioning

confidence: 99%

Biotransformation of Drugs in Human Skin

Svensson

2008

Drug Metab Dispos

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“…Although constitutive expression of xenobiotic-metabolizing enzymes has been detected in normal keratinocytes [2,3] the levels of drug-metabolizing enzymes are generally much lower in the skin than those in the liver and intestine [4][5][6][7]. Thus, skin permeability rather than drug metabolism appears to be the major barrier to topical bioavailability [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Xenobiotic transporters (ABCs and SLCs) have broad specificity and are involved in both uptake (influx) and secretion (efflux) of their substrates, thereby affecting their cellular disposition. Constitutive expression of multidrug-resistance associated proteins (MRP, ABCC) or solute carrier organic anion transporting polypeptides (OATPs) has been detected in human keratinocytes [2,3,10,11]. The expression of ABCB1 (multidrug resistance protein 1, P-glycoprotein or P-gp) has only been found after keratinocyte treatment with dexamethasone [2].…”

Section: Introductionmentioning

confidence: 99%

Characterization of SLC transporters in human skin

Alriquet¹,

Sevin²,

Gaborit³

et al. 2015

ADMET DMPK

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Most identified drug transporters belong to the ATP-binding Cassette (ABC) and Solute Carrier (SLC) families. Recent research indicates that some of these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin in the disposition of topically applied drugs and their involvement in drug-drug interactions. The aim of this work was to compare the expression in human skin (vs human hepatocytes and kidney) of SLC transporters included in the EMA guidance as the most likely clinical sources of drug interactions. The expression of SLC transporters in human tissues was analyzed by quantitative RT-PCR. Modulation of SLC47A1 and SLC47A2 (MATE1 and MATE2) expression was analyzed after treatment of human skin in organ-culture with rifampicin and UV irradiation. The expression of SLCO2B1 (OATPB), SLCO3A1 (OATPD), SLCO4A1 (OATPE), SLC47A1 and SLC47A2 (MATE1 and MATE2)

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“…Some of them, in particular weak contact sensitizers, are transformed into highly reactive species. It has been shown that the epidermis possesses multiple cytochrome P450 (CYP) isoenzymes that are able to metabolize xenobiotics to these highly reactive species (Baron et al, 2001). these enzymes are present in keratinocytes, which are the main cells of the epidermis, but they also are present in antigen presenting cells such as monocytes or dendritic cells.…”

Section: Qualitative and Quantitative Allergen-specific Protein Profimentioning

confidence: 99%

Advanced tests for skin and respiratory sensitization assessment

Rovida

Martin

Vivier

et al. 2013

ALTEX

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Denmark, aided by the vice-coordinator Hans-Ulrich Weltzien from the Max-Planck Institute for Immunobiology and epigenetics, Freiburg Germany. the ultimate goal of the Sens-it-iv project was the development of a set of in vitro methods for the assessment of the skin and respiratory sensitization potential of chemicals and proteins. the level of development was intended to be at the point to enter the pre-validation phase. After 66 months of work, it could be concluded that the goal was largely accomplished. Several advanced methods were evaluated extensively, and for some of them a detailed standard operating procedure (SOP) was established for pre-validation purposes. Other, less advanced methods contributed to our understanding of the mechanisms driving sensitization as well.Several opportunities were employed to assure dissemination of results. During the course of the project, 44 newsletters were released, presenting the main achievements of the project. Fly-1 Introduction

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Expression of Multiple Cytochrome P450 Enzymes and Multidrug Resistance-Associated Transport Proteins in Human Skin Keratinocytes

Cited by 211 publications

References 41 publications

Biotransformation of Drugs in Human Skin

Biotransformation of Drugs in Human Skin

Characterization of SLC transporters in human skin

Advanced tests for skin and respiratory sensitization assessment

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