Hormone-dependent enhancement in binding of oto- and nephrotoxic aminoglycoside antibiotics.

Abstract

Intraperitoneal administration of gentamicin (40 mg/ml) to the guinea pig is known to cause damage of the tissue of the kidneys and auditory organs. By indirect immunohistochemical staining with anti-gentamicin antiserum, those cells with high affinity to gentamicin in the auditory organs and kidneys were the hair cells in the cochlea and the epithelial cells in the renal tubules. The concentrations of gentamicin in the serum and perilymph of the guinea pig with tissue damage were found to be 2 and 0.6 mg/ml at the maximal levels, respectively, by high performance liquid chromatography. The same concentration of gentamicin, 2 mg/ml, also inhibited cell growth and resulted in cell damage of the renal tubule-derived cell lines, JTC-12 and MDCK. Among the antibiotics examined, i.e. streptomycin, gentamicin, fradiomycin and kanamycin, gentamicin showed the strongest effect on growth inhibition of the renal tubule-derived cells, when these cells were cultured in a medium with 5% fetal calf serum. Although the number of JTC-12 cells in the medium without fetal calf serum remained the same for a week, even with the addition of either gentamicin (0.5 mg/ml) or parathyroid hormone (2 mM) the coadministration of gentamicin and parathyroid hormone resulted in a loss of cells due to cellular death, and the amount of gentamicin bound onto the cells cultured with gentamicin plus parathyroid hormone was significantly higher than that with gentamicin alone. These results indicate that the expression of the receptor for gentamicin on the cell surface is greatly enhanced by hormonal stimulation.