H. Horiguchi et al., Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications, BLOOD, 96(12), 2000, pp. 3743-3747
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.