Functional polymorphism of human glutathione transferase A3: effects on xenobiotic metabolism and steroid biosynthesis.

Abstract

The alpha class glutathione transferase GSTA3-3 is involved in steroid biosynthesis and the metabolism of some xenobiotics. A bioinformatics approach was utilized to identify novel coding region polymorphisms in the glutathione transferase A3 gene (GSTA3). We describe an I71L polymorphism in GSTA3 that occurs at a low frequency in African populations. The activity of the leucine containing isoform was significantly reduced in a range of glutathione-conjugating reactions due to a diminished affinity for reduced glutathione, indicating that this allele could be implicated in disease caused by oxidative stress in steroidogenic tissue. By contrast, the delta(5)-androsten-3,17-dione isomerase activity of GSTA3-3 was not affected by this substitution, indicating that there is no direct effect on steroid synthesis. However, the L71 isoform displayed diminished stability at 45 degrees C. If this relative instability is mirrored in vivo, testosterone and progesterone synthesis may be affected in individuals carrying this allele.