title: Glutathione S-transferase genotype is associated with sensitivity to psoralen-ultraviolet A photochemotherapy.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The polymorphic human GSTs are associated with PUVA sensitivity. Further studies are required to examine the clinical relevance of these preliminary findings.
authors.affiliation: Photobiology Unit and Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. s.h.Ibbotson@dundee.ac.uk
authors.forename: S H
authors.initials: SH
authors.lastname: Ibbotson
authors.forename: R S
authors.initials: RS
authors.lastname: Dawe
authors.forename: A T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: S
authors.initials: S
authors.lastname: Weidlich
authors.forename: P M
authors.initials: PM
authors.lastname: Farr
authors.forename: J
authors.initials: J
authors.lastname: Ferguson
authors.forename: C R
authors.initials: CR
authors.lastname: Wolf
authors.forename: G
authors.initials: G
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000139:chemically induced; D005260:Female; D015870:Gene Expression; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008730:Methoxsalen / Q000008:administration & dosage* / Q000097:blood; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011701:PUVA Therapy / Q000379:methods*; D010787:Photosensitivity Disorders / Q000235:genetics; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000097:blood; D011110:Polymorphism, Genetic / Q000235:genetics*; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics*; D012008:Recurrence; D020218:Response Elements / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D008730:Methoxsalen; D017319:Photosensitizing Agents; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human