Microarray Analysis of Differentially-Expressed Genes Encoding CYP450 and Phase II Drug Metabolizing Enzymes in Psoriasis and Melanoma

Abstract

Cytochrome P450 drug metabolizing enzymes are implicated in personalized medicine for two main reasons. First, inter-individual variability in CYP3A4 expression is a confounding factor during cancer treatment. Second, inhibition or induction of CYP3A4 can trigger adverse drug–drug interactions. However, inflammation can downregulate CYP3A4 and other drug metabolizing enzymes and lead to altered metabolism of drugs and essential vitamins and lipids. Little is known about effects of inflammation on expression of CYP450 genes controlling drug metabolism in the skin. Therefore, we analyzed seven published microarray datasets, and identified differentially-expressed genes in two inflammatory skin diseases (melanoma and psoriasis). We observed opposite patterns of expression of genes regulating metabolism of specific vitamins and lipids in psoriasis and melanoma samples. Thus, genes controlling the turnover of vitamin D (CYP27B1, CYP24A1), vitamin A (ALDH1A3, AKR1B10), and cholesterol (CYP7B1), were up-regulated in psoriasis, whereas melanomas showed downregulation of genes regulating turnover of vitamin A (AKR1C3), and cholesterol (CYP39A1). Genes controlling abnormal keratinocyte differentiation and epidermal barrier function (CYP4F22, SULT2B1) were up-regulated in psoriasis. The up-regulated CYP24A1, CYP4F22, SULT2B1, and CYP7B1 genes are potential drug targets in psoriatic skin. Both disease samples showed diminished drug metabolizing capacity due to downregulation of the CYP1B1 and CYP3A5 genes. However, melanomas showed greater loss of drug metabolizing capacity due to downregulation of the CYP3A4 gene.

Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review

“…Based on calculations from 1,25(OH) 2 D production by perfused pig skin we ( Bikle et al, 1994 ) determined that epidermal production of 1,25(OH) 2 D could account for all the circulating 1,25(OH) 2 D found in anephric patients (or pigs) in the basal state or after supplementation with vitamin D or 25OHD. However, most if not all 1,25(OH) 2 D produced by the epidermis is used for autocrine or paracrine purposes with little contribution to the circulation even in hyperproliferative conditions such as psoriasis in which the expression of CYP27b1 is increased ( Sumantran et al, 2016 ). This is likely because of the rapid and extensive induction of CYP24 in these cells ( Sumantran et al, 2016 ), which limits the amount of secreted 1,25(OH) 2 D. However, in certain dermal conditions associated with inflammatory infiltrates such as slack skin disease, a T cell lymphoproliferative disease ( Karakelides et al, 2006 ), and subcutaneous fat necrosis of the newborn ( Farooque et al, 2009 ) the blood levels of calcium and 1,25(OH) 2 D increase in part due to the poorly regulated CYP27b1 activity of the inflammatory cells in the skin but not from the epidermal keratinocytes.…”

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…Generally, the downregulation of many other lipid biosynthesis enzymes promotes the unique role of CH25H [85]. In terms of substrate feedforward activation, the increase in 25-hydroxycholesterol may also account for the enhanced CYP7B1 expression as revealed in a comparative study on CYP450s in psoriasis and melanoma [86]. Interestingly, the TLR7/8 agonist imiquimod (IMQ) also signals via IRF3/7 and thereby induces an antiviral response in the respective psoriasis disease model [87].…”

Regulation of 25‐hydroxyvitamin D‐1‐hydroxylase and 24‐hydroxylase in keratinocytes by PTH and FGF23

“…The expression levels of 24(OH)ase vary in different cell types, sexes and ages . The expression levels of 1α(OH)ase altered in some diseases such as certain cancers and psoriasis . The expression of 24(OH)ase is regulated by 1,25(OH) 2 D in nearly all types of cells targeted by 1,25(OH) 2 D .…”