An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide.
OBJECTIVE
To investigate arsenic trioxide's renal toxicity, we analyzed the gene-expression patterns of primary renal and human kidney cells (HEK293 cell line) following exposure to arsenic trioxide. Moreover, we examined a potential renal toxic mechanism(s) of arsenic trioxide by using a toxicity-related gene and investigated potential treatments to reduce the renal toxicity of arsenic trioxide.


METHODS
Arsenic trioxide was exposed to primary renal and HEK293 cells, and the gene-expression analysis was conducted using DNA microarray. Then, reactive oxygen species inhibitors or alpha-lipoic acid were added to HEK293 cells exposed arsenic trioxide and cell viability was determined.


RESULTS
Expression of HMOX1 mRNA increased in a time- and dose-dependent manner, and translation of heme oxygenase 1 protein was also induced. Arsenic trioxide-induced cytotoxicity was inhibited by reactive oxygen species inhibitors. Moreover, superoxide anion was detected in arsenic trioxide-treated HEK293 cells. alpha-Lipoic acid ameliorated arsenic trioxide-induced cytotoxicity and reduced superoxide anion production in HEK293 cells, whereas it had no effect in promyelocytic leukemia cells (HL-60 cells and NB4 cells) and myeloma cells (KMS12BM cells and U266 cells).


CONCLUSIONS
Arsenic trioxide-induced renal toxicity is strongly associated with the increased expression of HMOX1, and the cytotoxic mechanisms of arsenic trioxide involves reactive oxygen species production as well as another pathway. These preliminary results suggest that alpha-lipoic acid may be a suitable agent for prevention or treatment of arsenic trioxide-induced renal toxicity.
Sasaki
Akira
A
Division of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan.
Oshima
Yasuo
Y
Fujimura
Akio
A
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000037:antagonists & inhibitors; D002374:Catalase / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D051547:Heme Oxygenase-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010087:Oxides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology; D013997:Time Factors
D001152:Arsenicals; D002395:Catecholamines; D048288:Imidazolines; D010087:Oxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013481:Superoxides; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D008063:Thioctic Acid; C011775:(3,4-dihydroxyphenylamino)-2-imidazoline; D002374:Catalase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000077237:Arsenic Trioxide