Isolated proximal tubular cells from rat kidney as an in vitro model for studies on nephrotoxicity. II. Alpha-methylglucose uptake as a sensitive parameter for mechanistic studies of acute toxicity by xenobiotics.

Many nephrotoxic agents exert their effect primarily on the cells of the proximal tubules. We isolated these cells and investigated whether the uptake of alpha-methylglucose (alpha-MG) could serve as a parameter to assess effects of nephrotoxins on the functional integrity of the cells. Agents that are acutely nephrotoxic in vivo, CD2+, Hg2+, UO22+, p-aminophenol, and bis-2,3-dibromopropylphosphate, inhibited alpha-MG uptake at low concentrations. Most agents that exert their effect in vivo with delay or only when used chronically (gentamicin, cephaloridine, phenacetin, and acetaminophen) inhibited alpha-MG uptake only at much higher concentrations; cisplatin, however, inhibited alpha-MG uptake at a low concentration. S-(1,1-Difluoro-2,2-dichloroethyl)-L-cysteine and its N-acetyl derivate, two metabolites of the nephrotoxic agent 1,1-dichloro-2,2-difluoroethylene, inhibit alpha-MG uptake. Aminooxyacetic acid, which prevents the formation of the ultimate toxic metabolite by inhibition of beta-lyase, abolished almost completely the toxicity of both compounds. The nephrotoxic conjugate of hexachlorobutadiene, S-(1,2,3,4,4-pentachlorobutadienyl)-glutathione, also inhibited alpha-MG uptake. The selective inhibitor of gamma-glutamyltranspeptidase, anthglutin, completely prevented this inhibition. These results indicate that the uptake of alpha-methylglucose by isolated proximal tubular cells from rat kidney is a useful parameter for the study of nephrotoxicity, since in vitro results reflect acute nephrotoxicity as observed in vivo.