Boogaard P J, Slikkerveer A, Nagelkerke J F, Mulder G J
Division of Toxicology, Leiden University, The Netherlands.
Biochem Pharmacol. 1991 Feb 1;41(3):369-75. doi: 10.1016/0006-2952(91)90533-b.
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.
据报道，顺铂（CDDP）诱导的肾毒性可通过铋离子（Bi3+）预处理而降低，Bi3+可选择性诱导肾金属硫蛋白（MT）。在本研究中，接受硝酸铋（50 μmol/kg/天，口服）8天的大鼠肾MT增加至对照的250%。体外实验表明，CDDP诱导毒性的降低是一种肾脏效应：与未处理大鼠的近端肾小管细胞（PTC）相比，从Bi3+处理大鼠分离的PTC中，CDDP以及HgCl2、CdCl2和对氨基酚的毒性降低。与CDDP、Hg2+和Cd2+毒性的降低相反，对氨基酚毒性的降低不能用MT的金属结合特性来解释。据报道，MT可作为自由基清除剂，这可能解释了我们的观察结果，因为对氨基酚毒性被认为是氧自由基产生的结果。体内实验表明，在给予CDDP（12 mg/kg）24小时后，Bi3+预处理大鼠的总体肾铂含量以及与肾MT结合的铂低于未处理大鼠，这表明肾毒性的降低不是由于Pt2+与肾MT结合增加所致。仅接受CDDP的大鼠肾超氧化物歧化酶（SOD）活性增加。这种SOD的升高可能是由于接触CDDP引起的过氧化损伤所致。在CDDP之前接受Bi3+的大鼠中SOD未升高这一事实表明：（i）过氧化作用导致CDDP诱导的肾毒性，（ii）MT的抗氧化特性是这种毒性降低的原因。
