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The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6\u2010hydroxymelatonin, and 6\u2010sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK\u2010II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild\u2010type and Abcg2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2<jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0mice was between 1.5 and 6\u2010fold higher compared to the wild\u2010type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (&gt;sixfold increase for 6\u2010sulfatoxymelatonin in Abcg2<jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild\u2010type compared with Abcg2<jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0lactating female mice. In addition, melatonin metabolites showed a higher milk\u2010to\u2010plasma ratio in wild\u2010type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.<\/jats:p>","DOI":"10.1111\/jpi.12849","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T07:33:10Z","timestamp":1671780790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites"],"prefix":"10.1111","volume":"74","author":[{"given":"Laura","family":"\u00c1lvarez\u2010Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences\u2010Physiology, Animal Health Institute (INDEGSAL), Faculty of Veterinary Medicine Universidad de Le\u00f3n Le\u00f3n 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