GST Polymorphisms and GST Enzyme Activity in Type 1 Myotonic Dystrophy

Abstract

chain reaction; +/+/+, gstm1, gst1 and gstm3 present; -/-/-, gstm1, gstt1 and gstm3 absent; ile/val and ile/ile=heterozygous and homozygous status of GSTP1 IntroductionMyotonic dystrophy (DM) is an autosomal dominant, multisystem trinucleotide repeat disorder. Myotonic dystrophy is clinically heterogeneous and at the molecular level at least two types can be distinguished: DM type 1 (DM1; Steinert disease) and DM type 2 (DM2; proximal myotonic myopathy (PROMM) or Ricker syndrome). DM1 is the most common form of muscular dystrophy in adults with an estimated incidence of 1:8000.1 Two different mutations are responsible for DM: DM1 (OMIM #160900) is caused by a (CTG)n repeat expansion in the 3'-untranslated region of the DMPK gene located within chromosome band 19ql3.3 2,3 while DM2 (OMIM #602688) is caused by a large (CCTG)n repeat expansion in intron l of the CNBP gene at chromosome 3q21. 4,5 GSTs activity involves in the pathogenesis of DM1 because it contains polymorphic trinucleotide repeat.6 Human GSTs represent a large and diverse super family of enzymes, with at least 13 GST enzymes belonging to five different families: mu, theta, alpha, pi, and gamma. The GSTM1 & GSTM3, GSTT1 and GSTP1 belong to the GSTmu, GSTtheta, and GSTpi categories of enzymes respectively. Glutathione S-transferases (GSTs) are phase II detoxifying enzymes that catalyze a variety of reduced glutathione-dependent reactions with electrophilic substrates, including active metabolites of carcinogens. 7 In particular, GSTM1, GSTM3, GSTP1 and GSTT1 are involved in detoxification of active metabolites of several potential carcinogens such as benzo [a]pyrene and other polycyclic aromatic hydrocarbons, monohalomethanes and ethylene oxide.7-9 It also play an important role in the functioning of antioxidant defences through reactive oxygen species (ROS) metabolism, in the repairing of damaged ROS and in the detoxification of several xenobiotics. 7,10 The absence of GSTT1 and GSTM1 enzyme activities is caused by homozygous deletion of the respective genes (null genotypes). 11,12 In the GSTM3 gene, the GSTM3*A wild-type allele and the GSTM3*B variant allele have been described. 8 GSTM3*B contains a recognition motif for the YY1 transcription factor, which has been postulated to regulate gene expression. 13 It was suggested that GSTM3*A and GSTM3*B are expressed at different levels and could therefore confer different efficiencies in the metabolism of carcinogens and toxic compounds.14 In the GSTP1 gene, 2 variant alleles, GSTP1*B and GSTP1*C, have been detected in addition to the wild-type allele GSTP1*A.9 Both variant alleles have an A-to-G transition at nucleotide 313, causing a change of isoleucine (Ile) to valine (Val) at codon 105. The specific activity and affinity for electrophilic substrates is altered in the Val variant.9 It is therefore plausible that hereditary differences in the activities of these enzymes, due to genetic polymorphisms. 8,9,11,12 Different GSTs polymorphism has been studied in various malignancies.15-18 However, there ...