{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:19:19Z","timestamp":1753877959704,"version":"3.41.2"},"reference-count":53,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017778","name":"Public Foundation of Chubu Science and Technology Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017778","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007655","name":"Aichi Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K16417","21K15319","23K06257"],"award-info":[{"award-number":["19K16417","21K15319","23K06257"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Vemurafenib (VEM) reportedly inhibits the mitochondrial respiratory chain and reduces ferrochelatase (FECH) activity, thereby causing VEM\u2010induced renal tubular toxicity. However, the exact mechanisms underlying VEM\u2010induced renal tubular toxicity remain unclear. In this study, we treated human renal proximal tubular epithelial cells with VEM to elucidate these mechanisms. VEM treatment for 24\u2009h resulted in cell damage, reduced cell viability, increased lactate dehydrogenase release and elevated the production of inflammatory cytokines. Transmission electron microscopy (TEM) and fluorescence microscopy revealed accumulation and enlargement of lysosome\u2010derived vacuoles and mitochondrial superoxide production. Although MitoTracker showed no change in the total mitochondrial volume, TEM indicated mitochondrial damage, including smaller and less visible mitochondria. Enhanced superoxide production was confirmed using mtSOX. The mitochondria\u2010specific antioxidant XJB\u20105\u2010131 partially alleviated VEM\u2010induced superoxide production and improved cell viability, indicating the role of superoxide in VEM\u2010induced renal tubular toxicity. The inhibition of lysosomal acidification by bafilomycin A1 did not mitigate VEM\u2010induced cytotoxicity, suggesting potential autophagy impairment. These findings highlight that mitochondrial dysfunction and lysosomal abnormalities are significant factors in VEM\u2010induced renal tubular toxicity, warranting further investigation into the relationship between their mechanisms, reduced FECH activity and potential renoprotective targets.<\/jats:p>","DOI":"10.1111\/bcpt.70015","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:05:37Z","timestamp":1741737937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Increased Mitochondrial Superoxide Level Is Partially Associated With Vemurafenib\u2010Induced Renal Tubular Toxicity"],"prefix":"10.1111","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5168-3011","authenticated-orcid":false,"given":"Akimasa","family":"Sanagawa","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmaceutics Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Takase","sequence":"additional","affiliation":[{"name":"Research Equipment Sharing Center Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1613984"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.02.008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.30"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.02780312"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13660"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.12.021"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2016.09.055"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103782"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408868"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28709"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.1713"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfv149"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010016\u20103086\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0149873"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.08.022"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2017.1557"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1347"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.1.281"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006080894"},{"issue":"4","key":"e_1_2_9_21_1","first-page":"336","article-title":"Regulation of Porphyrin and Heme Metabolism in the Kidney","volume":"25","author":"Woods J. S.","year":"1988","journal-title":"Seminars in Hematology"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfx146"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.97"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13944"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000001106"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b22\u201000322"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45361"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1992.299"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16079"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01270"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.01.109"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep23721"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jmicro.a050582"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jevs.2021.103620"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107218"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14419"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2022.03.012"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.17130"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6845"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.6b00199"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010020\u201002871\u20106"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1515609"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2012.11.018"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00859.2015"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00534.2020"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255784"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b01063"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.09.010"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030918"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113371"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010019\u20100388\u20104"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00043"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00969"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202402671"}],"container-title":["Basic &amp; Clinical Pharmacology &amp; Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcpt.70015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T01:57:00Z","timestamp":1744250220000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bcpt.70015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":53,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1111\/bcpt.70015"],"URL":"https:\/\/doi.org\/10.1111\/bcpt.70015","archive":["Portico"],"relation":{},"ISSN":["1742-7835","1742-7843"],"issn-type":[{"type":"print","value":"1742-7835"},{"type":"electronic","value":"1742-7843"}],"subject":[],"published":{"date-parts":[[2025,2,28]]},"assertion":[{"value":"2024-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70015"}}