{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:46:44Z","timestamp":1760575604252,"version":"build-2065373602"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Small intestinal epithelial vacuolation induced by a heteroaryldihydropyrimidine compound (HAP\u20101) was observed in rats but not in dogs at termination in screening toxicity studies, despite the plasma exposure being higher in dogs. To understand the species differences, investigational studies with multiple time points following single dose (SD) and 7\u2010day repeated dose (RD) were conducted in both species at doses resulting in comparable plasma exposures. In rats, epithelial vacuolation in the duodenum and jejunum were observed at all time points. In dogs, transient vacuolation was noted at 8\u00a0h post\u2010SD (SD_8h) and 4\u00a0h post\u2010RD (RD_4\u2009h), but not at termination (RD_24\u2009h). Special stains demonstrated lipid accumulation within enterocytes in both species and intracytoplasmic inclusion bodies in rats. Transmission electron microscopy identified these inclusion bodies as endoplasmic reticulum (ER) membranous structures. Transcriptomic analysis on jejunal mucosa at SD_8\u2009h and RD_24\u2009h revealed perturbations of lipid metabolism\u2010related genes at SD_8\u2009h in both species, but not at RD_24\u2009h in dogs. ER stress\u2010related gene changes at both time points were observed in rats only. Despite comparable HAP\u20101 plasma exposures, the duodenum and jejunum tissue concentrations of HAP\u20101 and acyl glucuronide metabolite were &gt;5\u2010 and &gt;30\u2010fold higher in rats than in dogs, respectively. In vitro, similar cytotoxicity was observed in rat and dog duodenal organoids treated with HAP\u20101. In conclusion, HAP\u20101\u2010induced intestinal epithelial vacuolation was related to lipid metabolism dysregulation in both species and ER\u2010related injuries in rats only. The species differences were likely related to the difference in intestinal exposure to HAP\u20101 and its reactive metabolite.<\/jats:p>","DOI":"10.1002\/jat.4550","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T22:18:36Z","timestamp":1697062716000},"page":"400-414","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Species differences in small intestinal exposure\u2010related epithelial vacuolation in rats and dogs treated with a heteroaryldihydropyrimidine molecule"],"prefix":"10.1002","volume":"44","author":[{"given":"Jieyu","family":"Dai","sequence":"first","affiliation":[{"name":"Preclinical Sciences and Translational Safety (PSTS) Janssen R&amp;D  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-2123","authenticated-orcid":false,"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Preclinical Sciences and Translational Safety (PSTS) Janssen R&amp;D  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Meng","sequence":"additional","affiliation":[{"name":"Preclinical Sciences and Translational Safety (PSTS) Janssen R&amp;D  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferran","family":"Jardi","sequence":"additional","affiliation":[{"name":"PSTS, Janssen Pharmaceutica NV  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Kourula","sequence":"additional","affiliation":[{"name":"PSTS, Janssen Pharmaceutica NV  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ly","family":"Pham","sequence":"additional","affiliation":[{"name":"PSTS, Janssen Pharmaceuticals Inc.  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