Mice pretreated with Zn have increased renal metallothionein (MT) levels and are protected from CdMT nephrotoxicity. To determine whether MT is important in this Zn-induced protection against CdMT-induced nephrotoxicity, MT-transgenic mice that have high levels of MT in their kidneys (10-fold over control mice) have been studied to determine whether they are resistant to CdMT-induced nephrotoxicity. Mice were injected with CdMT (0.1-0.6 mg Cd/kg, iv) and kidney injury was evaluated 24 hr later. CdMT produced renal toxicity in a dose-dependent manner. At a nephrotoxic dose of CdMT (0.4 mg Cd/kg), urinary protein and glucose excretion were increased 30- and 60-fold, respectively, in control mice. However, similar increases in protein and glucose excretion were also observed in MT-transgenic mice. CdMT also induced a similar dose-dependent proximal tubular cell necrosis in both control and MT-transgenic mice in a dose-dependent manner. Treatment of control mice with Zn (100 micromol/kg, sc x 2 days) increased renal MT to levels similar to those of untreated MT-transgenic mice and protected against CdMT-induced renal injury. Furthermore, when Zn (25-100 micromol/kg, sc) was given immediately before CdMT injection (i.e., without preinduction of MT), it was still effective in preventing CdMT nephrotoxicity. We conclude that Zn-induced protection against CdMT nephrotoxicity does not appear to be due to induction of renal MT.