title: 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.
abstract: 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.
authors: Division of Toxicology, Leiden University, The Netherlands.
authors: P J
authors: PJ
authors: Boogaard
authors: G J
authors: GJ
authors: Mulder
authors: J F
authors: JF
authors: Nagelkerke
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D002070:Butadienes / Q000633:toxicity; D017402:Chlorofluorocarbons; D002945:Cisplatin / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000633:toxicity; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008670:Metals / Q000633:toxicity; D008757:Methylglucosides / Q000493:pharmacokinetics*; D008759:Methylglycosides / Q000493:pharmacokinetics*; D010755:Organophosphates / Q000633:toxicity; D051381:Rats; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002070:Butadienes; D017402:Chlorofluorocarbons; D006846:Hydrocarbons, Halogenated; D008670:Metals; D008757:Methylglucosides; D008759:Methylglycosides; D010755:Organophosphates; D015262:Xenobiotics; C035185:bis(2,3-dibromopropyl)phosphate; C027020:methylglucoside; C054365:1,1-dichloro-2,2-difluoroethylene; C001335:hexachlorobutadiene; D002945:Cisplatin