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 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. (Blood. 2000;96:3743-3747)
Horiguchi
H
H
Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kayama
F
F
Oguma
E
E
Willmore
W G
WG
Hradecky
P
P
Bunn
H F
HF
D002104:Cadmium / Q000009:adverse effects / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D003035:Cobalt / Q000009:adverse effects / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004781:Environmental Exposure; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008628:Mercury / Q000009:adverse effects / Q000494:pharmacology; D019216:Metals, Heavy / Q000009:adverse effects / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000009:adverse effects / Q000494:pharmacology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019216:Metals, Heavy; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D002104:Cadmium; D004921:Erythropoietin; D003035:Cobalt; D008628:Mercury; D015032:Zinc; D002945:Cisplatin