Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases

Summary

Background

Treatment of common skin diseases such as psoriasis is complicated by differences between individuals in response to topical drug treatment and photochemo-therapy. Individuality in hepatic expression of drug-metabolising enzymes is an important determinant of systemic drug handling; we investigated whether similar variation in cutaneous gene expression contributes to individuality in response to topical therapies.

Methods

We used quantitative real-time RT-PCR to demonstrate the expression in skin of a recently identified cytochrome P450, CYP2S1, in healthy volunteers (n=27) and patients with psoriasis (n=29). We also investigated regulation of CYP2S1 by ultraviolet radiation, psoralen-ultraviolet A (PUVA), and topical drugs used to treat psoriasis.

Findings

We found that CYP2S1 is expressed in skin and showed pronounced individuality in constitutive expression of the enzyme and its induction after ultraviolet irradiation or topical drug treatment. Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, PUVA, coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3·38 [95% CI 2·64–4·34] times higher; p<0·0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid-metabolising enzyme.

Interpretation

These findings increase our understanding of the interaction between therapeutic agents and the skin and suggest a functional role for CYP2S1 in the metabolism of topical drugs and in mediating the response to photochemotherapy in psoriasis.

Introduction

Skin is the largest organ of the human body. There is increasing evidence that, in addition to its role as a physical barrier, skin is metabolically active. For example, it expresses a diverse and functional cytochrome P450 mono-oxygenase system.1, 2, 3, 4 Cytochrome P450s have been extensively studied in other organs, particularly liver, where they are essential catalysts of drug and xenobiotic metabolism. There is much inter-individual variation in the expression and activity of many hepatic P450s, resulting in differences in response to drug therapies and in the frequency of adverse drug reactions.⁵

Skin disease is common, with a third of the population affected at any time.⁶ Psoriasis affects about 2% of the population and is a major cause of morbidity and a substantial therapeutic challenge. Differences between individuals in response to topical drug treatment and ultraviolet radiation in the treatment of common skin disorders, such as psoriasis, are unpredictable. Although most patients tolerate drug therapy, some develop adverse effects or are resistant to treatment. Similarly, prediction of which patients will respond rapidly and well to ultraviolet B phototherapy or psoralen-ultraviolet A (PUVA) photochemotherapy and those who will be less responsive is not possible. An understanding of the factors that determine how individual patients respond to drugs or ultraviolet irradiation could help to make the outcome of treatment more predictable, thus reducing the frequency of side-effects and facilitating the selection of optimum treatment regimens on an individual basis.

One factor that may contribute to variation in response to treatment is inter-individual differences in the cutaneous expression of drug-metabolising enzymes and cytoprotective genes. Human skin is the first line of defence against environmental insult, and logically it should be rich in cytoprotective genes, thought to have evolved as an adaptive response to environmental challenge.⁷ Little is known about the expression and regulation of these genes in human skin, although they have been extensively studied in liver and in rodent and cell-culture models.

Cytochrome P450s are a multigene family of phase i mono-oxygenases which, together with their redox partner NADPH cytochrome P450 reductase, catalyse the oxidative metabolism of the vast majority of drugs and xenobiotics to which we are exposed.⁸ P450s in subfamilies CYP1 to CYP4 bring about most of the metabolism of foreign compounds, have unique but overlapping substrate specificities, and in general are regulated by substrate-induced activation of gene transcription.⁹ Expression of cytochrome P450s is highest in the liver, but many of these enzymes are also expressed in extrahepatic tissues.¹⁰ Expression of cytochrome P450s in human skin was first described more than 20 years ago¹¹ and was shown to be inducible after the topical application of crude coal tar, a source of polycyclic aromatic hydrocarbons, which are known to be potent inducers of P450 gene transcription.¹² Constitutive expression of CYP1A1 and the closely related isozyme CYP1B1 in human keratinocytes was recently confirmed by RT-PCR in a series of experiments that also identified mRNAs encoding CYP2B6, CYP2E1, and CYP3A5.¹ In a complementary study, mRNAs encoding CYP2A6, CYP2B6, and CYP3A4 were identified in primary human keratinocytes by rnase protection analysis.² Recent findings suggest that ultraviolet B irradiation can induce cutaneous expression of CYP1A1, CYP1B1,³ and CYP4A11.⁴ Greater understanding of cutaneous gene expression and regulation by topical chemicals and photochemotherapy and the ability to identify individual patients′ phenotypes could lead to a more rational approach to the treatment of common skin diseases.

Cytochrome P450 CYP2S1 has lately been identified from human genome databases. This enzyme is primarily expressed in extrahepatic tissues including the trachea, lung, and small intestine.¹³ CYP2S1 has been localised to chromosome 19q13·2, in a cluster with other P450s of the CYP2 family that are known to be involved in metabolism of drugs and xenobiotics.¹⁴ By use of quantitative real-time RT-PCR, we investigated CYP2S1 expression in human skin from healthy volunteers and patients with psoriasis. We also investigated whether there are differences between individuals in constitutive CYP2S1 expression and inducibility by ultraviolet radiation and drug treatment.