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Cytochrome P450 expression in human keratinocytes: an aryl hydrocarbon receptor perspective

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Abstract

The goal of this review is to stress the importance of the cytochrome P450 (CYP) superfamily that is expressed in human skin in the hope that it may stimulate further study in an intriguing topic that currently suffers from a relative dearth of information. Like the cells that line the respiratory and GI tracts [X. Ding, L.S. Kaminsky, Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts, Annu. Rev. Pharmacol. Toxicol. 43 (2003) 149–173], those present in human skin express a variety of CYPs that play important roles in xenobiotic, drug and steroid metabolism. In addition, a few CYPs, with potentially novel roles in metabolism and keratinocyte function, have recently been discovered that appear to be expressed in a keratinocyte-specific manner [L. Du, S.M. Hoffman, D.S. Keeney, Epidermal CYP2 family cytochromes P450, Toxicol. Appl. Pharmacol. 195 (2004) 278–287]. However, in preparing this review, it soon became apparent that in contrast to the progress made in understanding these events in the liver, relatively little is known in the human skin. Thus, while a number of tantalizing stories are beginning to emerge, they are far from complete.

In this review, a brief synopsis of the structure of skin and methods of culturing keratinocytes will be presented. This will be followed by an overview of the various CYPs and their putative regulators that have been currently identified to be expressed in human keratinocytes. Then, a more detailed analysis of CYP regulation that involves the aryl hydrocarbon receptor (AHR) signaling pathway will be offered in the hope that it may serve as a paradigm for other CYP regulatory studies in the skin. Finally, several clinical implications that may arise due to altered regulation of CYPs will be considered.

Section snippets

The skin: an important site of chemical exposure with self-renewing properties

As an important interface between an individual and his/her environment, the skin is a major site of direct exposure to many pharmaceutical and toxic agents. These exposures may occur occupationally through direct contact with adverse chemicals, environmentally through exposure to airborne pollutants, therapeutically through the administration of topical creams, or via a number of systemic exposures. While these exposures may result in a number of adverse outcomes such as contact dermatitis,

Expression of CYPs involved in xenobiotic/drug metabolism

Many of the CYPs that have been characterized to play major roles in xenobiotic/drug metabolism in the liver have also been identified in human skin (Table 1). Included in this group are the CYPs that are involved in the metabolism of many procarcinogens (i.e. CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6 and CYP3A4) and the majority of pharmaceutical drugs (i.e. CYP3A4/5 and CYP2D6) [12], [13], [14], [15]. Since in vitro culturing of keratinocytes, like many cell types, dramatically alters the

Induction of CYP expression in human keratinocytes

As shown in Table 1, the expression levels of distinct subsets of CYPs have been reported to be regulated by a number of nuclear receptors [33], [34], [35], [36], [37], [38]. However, it should be noted that the evidence presented here has been obtained from studies that were performed primarily in hepatocytes. Evidence that many of the ‘classic’ inducers of the CYPs are functional in human keratinocytes has been demonstrated [13]. This includes the induction of CYP2B by phenobarbital (CAR, [35]

Consequences of alterations in CYP expression

The fact that the skin expresses a variety of CYPs involved in diverse signaling pathways has pharmacological and toxicological consequences, many of which are undiscovered. The number of pharmaceutical products that are administered topically has increased dramatically in recent years. In addition to the standard creams and ointments that act as anti-inflammatories (i.e. dexamethasone, betamethasone and hydrocortisone), antibiotics (i.e. erythromycin), and antifungals (i.e. ketaconazole), a

Summary

This review has highlighted a number important aspects with respect to the CYPs expressed in human keratinocytes. A striking observation is the need for future research to close the gaps in our understanding of how CYPs and their regulation contribute to the etiology of skin diseases and their therapies.

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