Specific alterations of rat renal microsomal proteins induced by cephaloridine

In order to elucidate the molecular mechanisms of cephaloridine (CPH) nephrotoxicity, the effect of cephaloridine treatment on the protein composition of different subcellular fractions from rat kidney cortex was investigated. After intravenous treatment of male Wistar rats with 250-1200 mg/kg/d CPH for 1-3 days, kidneys were removed and the homogenate from renal cortex was separated into lysosomal, cytosolic and microsomal fractions. The polypeptide composition of the different subfractions was analyzed by one-dimensional SDS-gel electrophoresis and quantified by densitometry. Significant differences in the polypeptide composition between treated and non-treated animals were seen in the microsomal fraction. CPH-treatment induced a polypeptide with an apparent molecular weight of 44,000 and decreased the content of cytochrome P-450 isoenzymes in the microsomal fraction. Solubilization experiments showed that the CPH-induced microsomal polypeptide of molecular weight 44,000 is a peripheral membrane protein rather than an integral membrane protein. The induction of this protein by CPH was dose- and time-dependent. Preliminary experiments using the kidney slice technique indicate that the induction of this polypeptide correlates with the nephrotoxicity measured as decrease in renal cortical accumulation of organic ions. Thus, the results of the present study indicate that treatment of rats with CPH resulted in the induction of a microsomal polypeptide of molecular weight 44,000 which could be a sensitive parameter of cephaloridine nephrotoxicity.