119 Xenobiotic metabolism is triggered in atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease whose detailed pathogenesis remains elusive despite a clear involvement of epidermal barrier impairment and immune dysregulation. Xenobiotic metabolism is an important detoxification mechanism utilized by organs, including skin, to eliminate noxious exogenous and endogenous compounds and includes phase I and phase II enzymes as well as membrane transporters. Transcriptional control of xenobiotic metabolism is mediated via aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptors (PPARs). Previous work from our laboratory suggested that AD patients might have increased xenobiotic metabolism in the epidermis. Furthermore, transgenic mice overexpressing the constitutively activated human PXR displayed a Th2/Th17 skin inflammation and barrier dysfunction resembling AD. The goal of the current study is to decipher the role of xenobiotic metabolism in AD pathogenesis. Results show an increased expression of phase I and II enzymes, such as CYP1A1, CYP1B1 and CYP3A4, UGT1A1, UGT1A6, UGT1A9 and UGT1A10 in AD human epidermal equivalents (HEEs) when compared to control (CTL) HEEs. This is in line with the upregulation of upstream receptors namely AHR, PPARA and PPARG. In contrast, the transcription of membrane transporters (ABCC1, ABCC2, ABCB1) is downregulated. Immunofluorescence staining confirmed increased CYP1A1, CYP3A and UGT1A1 protein levels in AD HEEs. These results suggest a constitutive activation of the xenobiotic metabolism in AD, which can cause oxidative stress and inflammation. Accordingly, SOD2 is upregulated in AD HEEs when compared to CTL HEEs, indicating mitochondrial stress. Thus, upregulation of xenobiotic metabolism in nonlesional AD might contribute to disease pathogenesis.