Polymorphic electrophile response elements in the mouse glutathione S-transferase GSTa1 gene that confer increased induction

Induced transcription of a battery of stress response genes in mammals, inc luding several phase I and phase II drug metabolizing enzymes, is regulated by the electrophile responsive element (EpRE). Because previous directed m utagenesis of nucleotide motifs within the large, composite EpRE were shown to affect transcription factor binding and associated induced expression o f dependent genes, we hypothesized that naturally-occurring variation or po lymorphism in the EpRE sequence, if found, could affect the induced express ion of important protective genes like glutathione S-transferases, and that this could be an important determinant of cancer risk in humans and other mammals. To determine whether this occurred in nature, 32 strains and speci es of inbred mice were screened to examine the EpRE sequence present in the mGSTa1 promoter. Two species, Mus caroli and Mus spretus, showed TGAC --> TGGC mutations in the tandem TGAC motif. Inducibility (15-fold) of the vari ant Mus spretus EpRE sequence in a reporter gene construct in HepG2 cells w as significantly increased versus the wild-type EpRE sequence (8-fold). A c omparison of mGSTa1-induced expression in the livers of Mus spretus, Mus ca roli, and BALB/cJ mice showed the highest level of mGSTa1 mRNA in livers fr om the Mus spretus and Mus carolimice. This naturally-occurring polymorphis m within the EpRE domain is the first mutation with an associated phenotype to be reported within a promoter regulatory element of a drug metabolizing gene. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.