Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications

Both toxic exposure to cadmium and cancer therapy with cisplatin (CDDP) can induce anemia in patients owing to the insufficient production of erythrop oietin (EPO), Therefore, the effects of cadmium chloride (Cd) and CDDP in t he Hep3B human hepatoma cell line, which upregulates EPO expression in resp onse to hypoxia and cobalt (Co), were investigated. The induction of bindin g activity of the HIF-1 transcription factor and EPO mRNA expression and pr otein production were suppressed by Cd and CDDP in a dose-dependent manner with no apparent cell damage. Mercuric chloride also suppressed hypoxia- an d Go-induced EPO production, mRNA expression, and HIF-1 binding in a manner similar to Cd and CDDP, whereas zinc chloride suppressed Go-induced EPO pr oduction, mRNA expression, and HIF-1 binding but did not affect hypoxia ind uction or that observed after simultaneous exposure to hypoxia and Co, In c ontrast, lead and tin salts had no effect on HIF-1 activation or EPO expres sion. These results indicate that Cd and CDDP have a strong and specific in hibitory effect an hypoxia- and Go-induced signaling and EPO induction in h epatic cells. It is likely that these agents cause anemia by directly impac ting EPO production in the kidney. (C) 2000 by The American Society of Hema tology.