Quantitative real-time reverse transcription-polymerase chain reaction analysis of drug metabolizing and cytoprotective genes in psoriasis and regulation by ultraviolet radiation.
There are unpredictable inter-individual differences in response to ultraviolet radiation, used in the treatment of psoriasis and other common skin diseases. It is therefore essential that we attempt to identify phenotypic markers that correlate with individual treatment outcomes. Exposure of human skin to ultraviolet radiation results in the generation of reactive intermediates and oxidative stress. Hepatic drug metabolizing and cytoprotective genes are induced as an adaptive response to xenobiotics and reactive intermediates; as several of these genes are present in skin, we hypothesized that their cutaneous expression and regulation may be implicated in responses to ultraviolet radiation. We used quantitative real-time reverse transcription-polymerase chain reaction to investigate interindividual differences in the cutaneous expression of a variety of drug metabolizing and cytoprotective genes, including cytochrome P450s, glutathione S-transferases and drug transporters, and investigated the regulation of gene expression by ultraviolet radiation and in lesional psoriatic skin. We confirmed significant induction of cyclooxygenase 2 (mean 3.63-fold, range 0.14-22.6, p<0.0001) by ultraviolet radiation and showed more modest (approximately 2-fold) inductions of glutathione peroxidase, and novel inductions of glutathione S-transferase P1 and the drug transporter multidrug resistance associated protein-1. Glutathione S-transferase P1 (3.74-fold, 1.3-33.1, p<0.0001) and multidrug resistance associated protein-1 (4.06-fold, 1.3-24.8, p<0.0001) were also significantly increased in psoriatic plaque, as were P450 CYP2E1 (3.64-fold, 1-28.9 p<0.0001) and heme oxygenase-1 (10.19-fold, 2.9-49.7, p<0.0001), implying a differential adaptive response to oxidant exposure in lesional psoriatic skin. We found considerable interindividual variation in constitutive gene expression and inducibility, indicating that these genes may be associated with individuality in response to ultraviolet radiation.
Smith
Gillian
G
Biomedical Research Center, Photobiology Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
Dawe
Robert S
RS
Clark
Colin
C
Evans
Alan T
AT
Comrie
Muriel M
MM
Wolf
C Roland
CR
Ferguson
James
J
Ibbotson
Sally H
SH
D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D019610:Cytoprotection / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000528:radiation effects*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008660:Metabolism / Q000235:genetics; D008875:Middle Aged; D011701:PUVA Therapy; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology; D012879:Skin Physiological Phenomena; D014466:Ultraviolet Rays
D004364:Pharmaceutical Preparations