Carbon monoxide derived from heme oxygenase-2 mediates reduction of methylmercury toxicity in SH-SY5Y cells.
We examined the contribution of carbon monoxide (CO), an enzymatic product of heme oxygenase (HO), to methylmercury (MeHg) cytotoxicity in SH-SY5Y cells, because this gas molecule is reported to activate Nrf2, which plays a protective role against MeHg-mediated cell damage. Exposure of SH-SY5Y cells to CO gas resulted in protection against MeHg cytotoxicity, with activation of Nrf2. Interestingly, pretreatment with tin-protoporphyrin IX, a specific inhibitor of HO, caused a reduction in basal Nrf2 activity and thus enhanced sensitivity to MeHg. No induction of isoform 1 of HO (HO-1) was seen during MeHg exposure, but constitutive expression of isoform 2 (HO-2) occurred, suggesting that CO produced by HO-2 is the main participant in the protection against MeHg toxicity. Studies of small interfering RNA-mediated knockdown of HO-2 in the cells supported this possibility. Our results suggest that CO gas and its producing enzyme HO-2 are key molecules in cellular protection against MeHg, presumably through basal activation of Nrf2.
Toyama
Takashi
T
Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Shinkai
Yasuhiro
Y
Sumi
Daigo
D
Kumagai
Yoshito
Y
D002248:Carbon Monoxide / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
D008767:Methylmercury Compounds; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2