title: Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation.
abstract: Inhibitors of the mitochondrial respiratory chain complex I are suggested to exert anti-tumor activity on those tumors relying on oxidative metabolism and are therefore of interest to oncology research. Nevertheless, the safety profile of these inhibitors should be thoroughly assessed. Rotenone, a proven complex I inhibitor, has shown anti-carcinogenic activity in several studies. In this context rotenone was used in this study as a tool compound with the aim to identify suitable biomarker candidates and provide enhanced mechanistic insights into the molecular and cellular effects of complex I inhibitors. Rats were treated with 400 ppm rotenone daily for 1, 3 or 14 consecutive days followed by necropsy. Classical clinical endpoints, including hematology, clinical chemistry and histopathology with supporting investigations (FACS-analysis, enzymatic activity assays) were examined as well as gene expression analysis. Through these investigations, we identified liver, bone marrow and bone as target organs amongst approx. 40 organs evaluated at least histopathologically. Our results suggest blood analysis, bone marrow parameters, assessment of lactate in serum and glycogen in liver, and especially gene expression analysis in liver as useful parameters for an experimental model to help to characterize the profile of complex I inhibitors with respect to a tolerable risk-benefit balance.
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Heinz
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Alexius
authors.initials: A
authors.lastname: Freyberger
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lawrenz
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Schladt
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schmuck
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Wuppertal, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology*
chemical_list: D012402:Rotenone; D042967:Electron Transport Complex I