{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:40:49Z","timestamp":1778622049149,"version":"3.51.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T00:00:00Z","timestamp":1587427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T00:00:00Z","timestamp":1618012800000},"content-version":"am","delay-in-days":354,"URL":"http:\/\/rsc.li\/journals-terms-of-use"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Number JP17K08957"],"award-info":[{"award-number":["KAKENHI Grant Number JP17K08957"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["KAKENHI Grant Number JP17K08957"],"award-info":[{"award-number":["KAKENHI Grant Number JP17K08957"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Copper (Cu) is an essential trace element and acts as a redox cofactor for many enzymes; however, excess Cu is toxic to cells. Hydrogen sulfide (H2S) is a well-known toxic gaseous molecule, but it has various biological effects such as neuromodulation and vasodilation. H2S was recently demonstrated to be involved in the detoxification of heavy metals, including zinc and cadmium, suggesting that H2S helps to maintain the homeostasis of heavy metals in cells. However, it is unclear how H2S impacts cellular Cu dynamics. In this study, we examined the effects of H2S on Cu cytotoxicity. Human neuroblastoma SH-SY5Y cells were exposed to CuSO4 in the presence of the H2S donor NaHS. CuSO4 alone slightly induced cell injury, whereas the combination of CuSO4 and NaHS (Cu\/NaHS) increased Cu cytotoxicity. The Cu chelator bathocuproinedisulfonic acid mitigated Cu\/NaHS-induced cytotoxicity. Compared with CuSO4 alone, Cu\/NaHS markedly promoted ROS generation, mitochondrial dysfunction, and a decrease in ATP production. In addition, reporter assay using the metal responsive element (MRE)-driven reporter plasmid revealed that Cu\/NaHS augmented Cu-dependent MRE activation. The amount of intracellular Cu was significantly higher in cells treated with Cu\/NaHS than in those treated with CuSO4 alone. Moreover, Cu\/NaHS markedly suppressed the level of the Cu exporter ATP7A, but not ATP7B, protein, whereas the combination did not affect that of the Cu importer CTR1 protein. Taken together, we conclude that the marked decrease in the ATP7A protein level by Cu\/NaHS promotes intracellular Cu accumulation and leads to increased Cu cytotoxicity.<\/jats:p>","DOI":"10.1039\/d0mt00015a","type":"journal-article","created":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T01:43:05Z","timestamp":1586482985000},"page":"868-875","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Hydrogen sulfide increases copper-dependent neurotoxicity<i>via<\/i>intracellular copper accumulation"],"prefix":"10.1093","volume":"12","author":[{"given":"Norika","family":"Goto","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7928-002X","authenticated-orcid":false,"given":"Hirokazu","family":"Hara","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mao","family":"Kondo","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Kamiya","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Okuda","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyama-kita, Higashinada, Kobe 658-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuo","family":"Adachi","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Fax: +81-58-230-8105; Tel: +81-58-230-8100"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,4,21]]},"reference":[{"key":"2021121004462114400_cit1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12964-018-0277-3","article-title":"Copper signalling: causes and consequences","volume":"16","author":"Kardos","year":"2018","journal-title":"Cell Commun. 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Biol."},{"key":"2021121004462114400_cit5","first-page":"147251","article-title":"Copper and copper proteins in Parkinson\u2019s disease","author":"Montes","year":"2014","journal-title":"Oxid. Med. Cell. Longevity"},{"key":"2021121004462114400_cit6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.abb.2007.04.021","article-title":"Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis","volume":"463","author":"La Fontaine","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"2021121004462114400_cit7","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1136\/jmg.2007.052746","article-title":"Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes","volume":"44","author":"de Bie","year":"2007","journal-title":"J. Med. 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