Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity.
3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10-50 muM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO). D3T treatment also caused elevation of SOD, GSH, GR, GPx and GST in the isolated mitochondria. We also observed a time-dependent induction by D3T of mRNA expression for Cu,ZnSOD, MnSOD, gamma-glutamylcysteine ligase, GR, GSTA1, GSTM1, NQO1, AR, and HO-1. Pretreatment with D3T conferred concentration-dependent protection against cell injury induced by xanthine oxidase (XO)/xanthine, H(2)O(2), 3-morpholinosydnonimine, 4-hydroxy-2-nonenal, and doxorubicin. Pretreatment with D3T also reduced the formation of intracellular reactive oxygen species by XO/xanthine, H(2)O(2), and doxorubicin. In conclusion, this study demonstrated that D3T potently upregulated many antioxidants and phase 2 enzymes in human cardiomyocytes, which was accompanied by increased resistance to oxidative/electrophilic stress and doxorubicin toxicity.
Zhu
Hong
H
Virginia Tech Corporate Research Center, Blacksburg, VA 24060, USA. hzhu@vcom.vt.edu
Jia
Zhenquan
Z
Zhou
Kequan
K
Misra
Hara P
HP
Santo
Arben
A
Gabrielson
Kathleen L
KL
Li
Yunbo
Y
D000447:Aldehydes / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D006801:Humans; D050217:Metabolic Detoxication, Phase II; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000633:toxicity
D000447:Aldehydes; D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; C002385:linsidomine; D004317:Doxorubicin; D008981:Molsidomine; D014969:Xanthine Oxidase; C027576:4-hydroxy-2-nonenal; C049325:1,2-dithiol-3-thione