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?
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.
Boogaard
P J
PJ
Division of Toxicology, Leiden University, The Netherlands.
Slikkerveer
A
A
Nagelkerke
J F
JF
Mulder
G J
GJ
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
D000975:Antioxidants; D008668:Metallothionein; D013482:Superoxide Dismutase; D005978:Glutathione; D002945:Cisplatin; D001729:Bismuth