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The intricate relationship between the loss of circadian rhythm and its influence on the tolerability and pharmacokinetic properties of anticancer drugs is poorly understood. In our study, we investigated the effects of oxaliplatin, a commonly used anticancer drug, on <jats:italic>Cry1<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup> and <jats:italic>Cry2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup> mice (<jats:italic>Cry<\/jats:italic> DKO mice) under darkness conditions, where they exhibit free-running phenotype. We administered oxaliplatin at a dosage of 12\u00a0mg\/kg\/day at two distinct circadian times, CT8 and CT16, under constant darkness conditions to <jats:italic>Cry<\/jats:italic> DKO mice and their wild type littermates. Our results revealed a striking disparity in oxaliplatin tolerance between <jats:italic>Cry<\/jats:italic> DKO mice and their wild-type counterparts. Oxaliplatin exhibited severe toxicity in <jats:italic>Cry<\/jats:italic> DKO mice at both CT8 and CT16, in contrast to the wild type mice. Pharmacokinetic analyses suggested that such toxicity was a result of high concentrations of oxaliplatin in the serum and liver of <jats:italic>Cry<\/jats:italic> DKO mice after repeated dose injections. To understand the molecular basis of such intolerance, we performed RNA-seq studies using mouse livers. Our findings from the RNA-seq analysis highlighted the substantial impact of circadian rhythm disruption on gene expression, particularly affecting genes involved in detoxification and xenobiotic metabolism, such as the <jats:italic>Gstm<\/jats:italic> gene family. This dysregulation in detoxification pathways in <jats:italic>Cry<\/jats:italic> DKO mice likely contributes to the increased toxicity of oxaliplatin. In conclusion, our study highlights the crucial role of an intact molecular clock in dictating the tolerability of oxaliplatin. These findings emphasize the necessity of considering circadian rhythms in the administration of anticancer drugs, providing valuable insights into optimizing treatment strategies for cancer patients.<\/jats:p>","DOI":"10.1007\/s00204-025-03968-7","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:18:18Z","timestamp":1738646298000},"page":"1417-1429","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The impact of circadian rhythm disruption on oxaliplatin tolerability and pharmacokinetics in Cry1\u2212\/\u2212Cry2\u2212\/\u2212 mice under constant darkness"],"prefix":"10.1007","volume":"99","author":[{"given":"Yasemin Kubra","family":"Akyel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narin Ozturk","family":"Seyhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eeref","family":"G\u00fcl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"\u00c7elik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali Cihan","family":"Ta\u015fk\u0131n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Selby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziz","family":"Sancar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim Halil","family":"Kavakli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9891-5588","authenticated-orcid":false,"given":"Alper","family":"Okyar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"issue":"6","key":"3968_CR1","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1056\/NEJMra1802337","volume":"384","author":"R Allada","year":"2021","unstructured":"Allada R, Bass J (2021) Circadian mechanisms in medicine. 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