Maturation of cochlear glutathione- S-transferases correlates with the end of the sensitive period for ototoxicity

Abstract

The developing mammalian cochlea is especially sensitive to chemical toxins. In rats, the period of increased sensitivity falls roughly between postnatal days (P) 8 and 28. One unexplored hypothesis for this ‘sensitive period’ is that young cochleas may have immature complements of detoxification enzymes. Glutathione- S-transferases (GSTs) are a family of detoxification enzymes which catalyze the conjugation of many xenobiotics to glutathione. Using high performance liquid chromatography (HPLC), we measured the concentrations of soluble GST isoforms in cochleas of developing Fischer 344 rats. At P1, the concentration of isoform rGSTP1 was 9 pmol/mg protein. That of the remaining isoforms studied was low, <2 pmol/mg protein, and, except for rGSTA3, remained so throughout the period of study. At P2, immunolabelling visualized rGSTP1 in the stria vascularis, Reissner’s membrane, spiral limbus and organ of Corti. From P1 to P28, rGSTP1 increased to 15 pmol/mg protein and was detected additionally in satellite cells of the spiral ganglion and in the spiral ligament. From P7 to P28, rGSTA3 increased 8-fold (3–24 pmol/mg protein), became the predominant isoform in the adult organ and localized to pillar cells, the limbus and the spiral ligament. In the vestibule, rGSTP1 predominated, although rGSTA3 increased slightly over time. These observations suggest that biochemical immaturity in detoxification enzymes in the cochlea may contribute to the increased sensitivity to ototoxins during development and that differences in detoxification enzymes between cells in the cochlea and between inner ear organs may underlie differences in susceptibility to ototoxins.