title: The role of metallothionein in the reduction of cisplatin-induced nephrotoxicity by Bi3(+)-pretreatment in the rat in vivo and in vitro. Are antioxidant properties of metallothionein more relevant than platinum binding?
abstract: Nephrotoxicity induced by cisplatin (CDDP) was reported to be reduced by Bi3(+)-pretreatment, which selectively induces renal metallothionein (MT). In the present study renal MT had increased to 250% of control in rats that received bismuth subnitrate (50 mumol/kg/day, orally) for 8 days. In vitro experiments demonstrated that the reduction of CDDP-induced toxicity is a renal effect: in proximal tubular cells (PTC) isolated from Bi3(+)-treated rats the toxicity of CDDP, and also of HgCl2, CdCl2 and p-aminophenol, was reduced as compared to PTC from untreated rats. In contrast to the reduction in CDDP, Hg2+ and Cd2+ toxicity, the reduction in p-aminophenol toxicity cannot be explained by the metal-binding properties of MT. MT was reported to act as a free radical scavenger, which may explain our observation since p-aminophenol toxicity is thought to be a consequence of the generation of oxygen radicals. In vivo experiments showed that the overall renal Pt-content as well as the Pt bound to renal MT is lower in Bi3(+)-pretreated rats than in untreated rats, 24 hr after administration of CDDP (12 mg/kg), suggesting that the reduction in nephrotoxicity is not due to increased binding of Pt2+ to renal MT. Renal superoxide dismutase (SOD) activity was increased in rats that had only received CDDP. Such a rise in SOD may result from peroxidative damage caused by exposure to CDDP. The fact that SOD was not elevated in rats that received Bi3+ prior to CDDP suggests that (i) peroxidation contributes to CDDP-induced nephrotoxicity and (ii) the anti-oxidant properties of MT are responsible for the reduction of this toxicity.
authors.affiliation: Division of Toxicology, Leiden University, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Boogaard
authors.forename: A
authors.initials: A
authors.lastname: Slikkerveer
authors.forename: J F
authors.initials: JF
authors.lastname: Nagelkerke
authors.forename: G J
authors.initials: GJ
authors.lastname: Mulder
mesh_terms: D000818:Animals; D000975:Antioxidants; D001729:Bismuth / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D003600:Cytosol / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008668:Metallothionein; D013482:Superoxide Dismutase; D005978:Glutathione; D002945:Cisplatin; D001729:Bismuth