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The aim of this study was to elucidate the putative pathomechanism explaining the association between the genetic polymorphism with the alleles <jats:italic>CYP2C8*2<\/jats:italic> and <jats:italic>*3<\/jats:italic> causing low CYP2C8 activity, and disturbed periodontal remodelling in periodontal fibroblasts cultured from patients undergoing orthodontic treatment. CYP2C8 activity, enzyme expression and substrate metabolism were detected in human periodontal fibroblast cultures. Zoledronic acid caused enhanced reactive oxygen species (ROS) production in periodontal fibroblasts, which was enhanced by arachidonic acid as inflammatory signal. Enhanced bisphosphonate\u2010induced uncoupling of the CYP2C8 enzyme was detected in the variant allele (<jats:italic>CYP2C8*3<\/jats:italic>) with the result of increased H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> production and lowered substrate oxidation. Conversely, substrate (amodiaquine) addition led to decreased H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> production in isolated CYP2C8 enzymes, but in CYP2C8*3 enzyme, increased H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> was still detected, especially in presence of arachidonic acid. <jats:italic>CYP2C8<\/jats:italic> variants leading to decreased enzyme activity in substrate oxidation may enhance ROS production by reaction uncoupling, and thus, contribute to difficulties in orthodontic treatment and the risk of side effects of antiresorptive drugs.<\/jats:p>","DOI":"10.1111\/bcpt.13681","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T23:38:50Z","timestamp":1636155530000},"page":"132-140","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of cytochrome P450 2C8 genetic polymorphism and epoxygenase uncoupling in periodontal remodelling affecting orthodontic treatment"],"prefix":"10.1111","volume":"130","author":[{"given":"Sabrina","family":"Yamoune","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"},{"name":"Research Division Federal Institute for Drugs and Medical Devices (BfArM)  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Wintz","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Niederau","sequence":"additional","affiliation":[{"name":"Orthodontic Clinic University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogerio B.","family":"Craveiro","sequence":"additional","affiliation":[{"name":"Orthodontic Clinic University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Wolf","sequence":"additional","affiliation":[{"name":"Orthodontic Clinic University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1566-8156","authenticated-orcid":false,"given":"Julia","family":"Stingl","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2019.07.016"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.08.009"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.9.3.277"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/JPER.19-0385"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184626"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.8b03401"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-188300"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13492"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60338-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00056-018-0145-1"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15281-0"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-019-03111-8"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.300.2.399"},{"issue":"2","key":"e_1_2_8_15_1","first-page":"1440","article-title":"Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice","volume":"17","author":"Tamaoka J","year":"2019","journal-title":"Exp Ther Med"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cotox.2017.10.003"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2018.05.014"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200110000-00006"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011411"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-015-1679-x"}],"container-title":["Basic &amp; 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