Epidermal CYP2 family cytochromes P450

Abstract

Skin is the largest and most accessible drug-metabolizing organ. In mammals, it is the competent barrier that protects against exposure to harmful stimuli in the environment and in the systemic circulation. Skin expresses many cytochromes P450 that have critical roles in exogenous and endogenous substrate metabolism. Here, we review evidence for epidermal expression of genes from the large CYP2 gene family, many of which are expressed preferentially in extrahepatic tissues or specifically in epithelia at the environmental interface. At least 13 CYP2 genes (CYP2A6, 2A7, 2B6, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2R1, 2S1, 2U1, and 2W1) are expressed in skin from at least some human individuals, and the majority of these genes are expressed in epidermis or cultured keratinocytes. Where epidermal expression has been localized in situ by hybridization or immunocytochemistry, CYP2 transcripts and proteins are most often expressed in differentiated keratinocytes comprising the outer (suprabasal) cell layers of the epidermis and skin appendages. The tissue-specific transcriptional regulation of CYP2 genes in the epidermis, and in other epithelia that interface with the environment, suggests important roles for at least some CYP2 gene products in the production and disposition of molecules affecting competency of the epidermal barrier.

Introduction

Enzymes of the cytochrome P450 superfamily have numerous important roles in exogenous and endogenous substrate metabolism (e.g., therapeutic drugs, xenobiotics, fatty acids, eicosanoids, sterols, steroids, vitamins A and D) (Nebert and Russell, 2002). It is now known that many cytochromes P450 (CYP gene products) are expressed in cutaneous tissues and are therefore relevant to dermatotoxicology and human health (Mukhtar, 1992). This review is limited to discussing genes from the large CYP2 gene family, many of which are preferentially expressed in extrahepatic tissues, with an emphasis on the CYP2 genes specifically expressed in epithelial tissues at the environmental interface. Tissue-specific transcriptional regulation at these sites suggests important roles for at least some CYP2 gene products in epithelial barrier functions in skin and in other organ systems such as the nasal, respiratory, oral, and digestive systems Ding and Kaminsky, 2003, Ladd et al., 2003, Smith et al., 2003.

Historically, cutaneous cytochromes P450 were studied from the perspective of polycyclic aromatic hydrocarbon (PAH) metabolism. Cutaneous PAH metabolism has been a critical component of the multistage model of mouse skin carcinogenesis, the origins of which predate the discovery of cytochromes P450 (in the late 1950s) by at least three decades (reviewed by Conney, 2003, DiGiovanni, 1992, Mukhtar, 1992). Since CYP1 family enzymes are efficient PAH hydroxylases and metabolically activate procarcinogens leading to skin tumors (Ahmad et al., 1996), these have been by far the most extensively studied cytochromes P450 in cutaneous tissues.

The activities of cutaneous cytochromes P450 that metabolize foreign compounds were studied extensively throughout the 1980s (reviewed by Bickers, 1991, Hotchkiss, 1992, Kao and Carver, 1991, Merk et al., 1996). At the same time, the multiplicity and diversity of the CYP gene superfamily were being discovered by molecular cloning approaches (Nebert et al., 1991). Two seminal observations from this period were that the epidermis is the major site of drug metabolism in skin (Bickers et al., 1982), and that within the epidermis, activities are greatest in the more differentiated keratinocytes (Reiners et al., 1991). In the 1990s, these advances led to the identification of specific CYP genes expressed in skin, the products of which were likely responsible for the cutaneous drug metabolism reported previously (Mukhtar, 1992). Important advances in the present decade include the identification of cytochromes P450 involved in endogenous substrate metabolism and information on their roles in epithelial differentiation and in vivo functions. Future progress will likely include the identification of cytochromes P450 involved in detoxification and epithelial barrier repair after injury, in response to specific physical, chemical, and biological agents.

The CYP2 gene family, which encodes a significant fraction of all cytochromes P450 in vertebrates, encompasses a large number of genes in humans that are classified into 13 subfamilies (Nelson, 2003). The CYP2 subfamilies that contain one or a few member loci generally encode orthologous genes in human and rodent species (CYP2E, 2F, 2G, 2R, 2S, 2T, 2U, 2W). Other CYP2 subfamilies, however, have undergone relatively recent expansions in some mammalian lineages, resulting in variable numbers of loci per species whose orthologous relationships are obscure (CYP2A, 2B, 2C, 2D, 2J). Here we review data reported on expression of specific CYP2 genes in human epidermis, based on nucleic acid and immunocytochemical studies. Results obtained using mouse or rat epidermis are included where they complement or fill voids in the literature. With a few exceptions, relatively little is known about CYP2 genes in other mammalian species (Nelson, 2003). A comprehensive picture of all CYP loci in a given species requires nearly complete genomic sequencing and is therefore currently available only for humans and mice (Nelson et al., 2004).