Glutathione S-transferase genotype is associated with sensitivity to psoralen-ultraviolet A photochemotherapy

S. H. Ibbotson, R. S. Dawe, A. T. Dinkova-Kostova, S. Weidlich, P. M. Farr, J. Ferguson, C. R. Wolf, G. Smith

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    Abstract

    Summary Background There is marked interpatient variation in responses to psoralen-ultraviolet A (PUVA) photochemotherapy. Identification of molecular biomarkers of PUVA sensitivity may facilitate treatment predictability. The glutathione S-transferases (GSTs) influence cutaneous defence against UV radiation-induced oxidative stress and are therefore candidate biomarkers of PUVA sensitivity. Several human GSTs, including GSTM1 and GSTT1, are polymorphic, and null polymorphisms have been associated with increased UVB erythemal sensitivity and skin cancer risk. PUVA also increases skin cancer risk. Objectives To investigate the effect of GST genotype on PUVA sensitivity. Methods We investigated GST genotype in patients starting PUVA (n = 111) and the effects of 8-methoxypsoralen (8-MOP) on antioxidant response element (ARE)-regulated gene expression in mammalian cells. Results Lower minimal phototoxic doses (MPD) (P = 0·022) and higher serum 8-MOP concentrations (P = 0·052) were seen in GSTM1-null allele homozygotes compared with patients with one or two active alleles. In a subset of patients with psoriasis (n = 50), the GSTM1 genotype was not associated with PUVA outcomes, although MPD [hazard ratio (HR) 1·37; 95% confidence interval (CI) for HR 1·15-1·64] and GSTT1-null (HR 2·39; 95% CI for HR 1·31-4·35) and GSTP1b (HR 1·96; 95% CI for HR 1·10-3·51) genotypes were associated with clearance of psoriasis in this patient group. Exposure of mammalian cells to 8-MOP induced gene expression via the ARE, a regulatory sequence in promoters of cytoprotective genes including GSTs, suggesting that these genes may be implicated in 8-MOP metabolism. Conclusion The polymorphic human GSTs are associated with PUVA sensitivity. Further studies are required to examine the clinical relevance of these preliminary findings.
    Original languageEnglish
    Pages (from-to)380-388
    Number of pages9
    JournalBritish Journal of Dermatology
    Volume166
    Issue number2
    DOIs
    Publication statusPublished - Feb 2012

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    Keywords

    • Young Adult
    • Erythema
    • Photosensitivity Disorders
    • Polymorphism, Genetic
    • Dose-Response Relationship, Drug
    • Humans
    • Gene Expression
    • Glutathione Transferase
    • Aged
    • PUVA Therapy
    • Recurrence
    • Genotype
    • Glutathione S-Transferase pi
    • Photosensitizing Agents
    • Psoriasis
    • Methoxsalen
    • Oxidative Stress
    • Adult
    • Treatment Outcome
    • Middle Aged
    • Response Elements
    • Adolescent
    • Female
    • Male

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