Hypervariable area in the 5' flanking region of GSTP1, previously reported as a minisatellite repeat

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Glutathione S transferases are dimeric molecules, catalysing the conjugation of activated (acetylated, alkylated, hydroxylated, oxygenated) molecules of xenobiotics to glutathione. Large deletions in the genes coding for some of the enzymes (GSTM1, GSTT1) are known and related to deficiency in conjugation of the metabolites of xenobiotics. Alterations in glutathione metabolism have been shown to have an important impact on the cytotoxicity of various free radical-producing anticancer drugs, like adriamycin. The overexpression of GSTP1 was shown to be involved in the acquisition of resistance to anticancer drugs like adriamycin, cisplatin, melphalan and etoposide. Two polymorphisms in GSTP1 are known: a point mutation in exon 5 with a possible functional role, leading to changes in the kinetic properties of the enzyme, and a repeat of AAAAT in the 5' untranslated region immediately upstream of an extensively methylated CpG island. Poly AT-rich repeats are implicated as differential enhancers of transcriptional activation. Here we report that the repeat in the AT-rich area of the 5' untranslated region is further degenerated by insertions of CAC, ATT and other motifs, and describe a detailed analysis of the polymorphism with a putative role in the regulation of transcriptional activation.