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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3743-3747
HEMATOPOIESIS
Cadmium and platinum suppression of erythropoietin production in
cell culture: clinical implications
Hyogo Horiguchi,
Fujio Kayama,
Etsuko Oguma,
William G. Willmore,
Pavel Hradecky, and
H. Franklin Bunn
From the Hematology Division, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA; the Department of
Public Health, Faculty of Medicine, Fukushima Medical University,
Fukushima, Japan; and the Division of Environmental Immunology
and Toxicology and CREST, JST, and the Department of Health
Science, Jichi Medical School, Tochigi, Japan.
Both toxic exposure to cadmium and cancer therapy with cisplatin
(CDDP) can induce anemia in patients owing to the insufficient production of erythropoietin (EPO). Therefore, the effects of cadmium
chloride (Cd) and CDDP in the Hep3B human hepatoma cell line, which
up-regulates EPO expression in response to hypoxia and cobalt (Co),
were investigated. The induction of binding activity of the HIF-1
transcription factor and EPO mRNA expression and protein production
were suppressed by Cd and CDDP in a dose-dependent manner with no
apparent cell damage. Mercuric chloride also suppressed hypoxia- and
Co-induced EPO production, mRNA expression, and HIF-1 binding in a
manner similar to Cd and CDDP, whereas zinc chloride suppressed
Co-induced EPO production, mRNA expression, and HIF-1 binding but did
not affect hypoxia induction or that observed after simultaneous
exposure to hypoxia and Co. In contrast, lead and tin salts had no
effect on HIF-1 activation or EPO expression. These results indicate
that Cd and CDDP have a strong and specific inhibitory effect on
hypoxia- and Co-induced signaling and EPO induction in hepatic cells.
It is likely that these agents cause anemia by directly impacting EPO
production in the kidney.
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