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

The developing mammalian cochlea is especially sensitive to chemical toxins . In rats, the period of increased sensitivity falls roughly between postna tal days (P) 8 and 28. One unexplored hypothesis for this 'sensitive period ' is that young cochleas may have immature complements of detoxification en zymes. Glutathione-S-transferases (GSTs) are a family of detoxification enz ymes which catalyze the conjugation of many xenobiotics to glutathione. Usi ng high performance liquid chromatography (HPLC), we measured the concentra tions of soluble GST isoforms in cochleas of developing Fischer 344 rats. A t P1, the concentration of isoform rGSTP1 was 9 pmol/mg protein. That of th e 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 limb us and organ of Corti. From P1 to P28, rGSTP1 increased to 15 pmol/mg prote in 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 p mol/mg protein), became the predominant isoform in the adult organ and loca lized 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 dur ing development and that differences in detoxification enzymes between cell s in the cochlea and between inner ear organs may underlie differences in s usceptibility to ototoxins. (C) 1999 Elsevier Science B.V. All rights reser ved.