An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide

• Published in: Experimental hematology 2007-02, Vol.35 (2), p.252-262
• Main Authors: Sasaki, Akira, Oshima, Yasuo, Fujimura, Akio
• Format: Article
• Language: English
• Subjects: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt - pharmacology; Advanced Basic Science; Arsenicals - antagonists & inhibitors; Catalase - pharmacology; Catecholamines - pharmacology; Cell Death - drug effects; Cell Survival - drug effects; Cells, Cultured; Cluster Analysis; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Hematology, Oncology and Palliative Medicine; Heme Oxygenase-1 - drug effects; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HL-60 Cells; Humans; Imidazolines - pharmacology; Kidney Cortex - cytology; Kidney Cortex - drug effects; Oligonucleotide Array Sequence Analysis - methods; Oxides - antagonists & inhibitors; Oxides - toxicity; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Superoxides - antagonists & inhibitors; Superoxides - metabolism; Thioctic Acid - pharmacology; Time Factors
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2006.10.004

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. Materials and 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 α-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. α-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 α-lipoic acid may be a suitable agent for prevention or treatment of arsenic trioxide-induced renal toxicity.