TY - JOUR
T1 - Carbon monoxide derived from heme oxygenase-2 mediates reduction of methylmercury toxicity in SH-SY5Y cells
AU - Toyama, Takashi
AU - Shinkai, Yasuhiro
AU - Sumi, Daigo
AU - Kumagai, Yoshito
N1 - Funding Information:
This work supported by a Grant-in-Aid (# 20241015 to Y. K.) for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan . We thank Dr. Akira Yasutake, Department of Basic Medical Sciences, National Institute for Minamata Disease, for helpful advice in the experiment, and Prof. Ken Itoh, Center for Advanced Medical Research, Hirosaki University School of Medicine, for the kind provision of ARE-luciferase and helpful advice on the experimental procedures.
PY - 2010/11/15
Y1 - 2010/11/15
N2 - 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.
AB - 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.
KW - Carbon monoxide
KW - Heme oxygenase
KW - Methylmercury
KW - Nrf2
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U2 - 10.1016/j.taap.2010.08.021
DO - 10.1016/j.taap.2010.08.021
M3 - Article
C2 - 20807546
AN - SCOPUS:77957875459
VL - 249
SP - 86
EP - 90
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -