title: Genotoxic properties of XLR-11, a widely consumed synthetic cannabinoid, and of the benzoyl indole RCS-4.
abstract: Aim of this study was the investigation of the genotoxic properties of XLR-11 [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone, a widely consumed synthetic cannabinoid (SC), and of the benzoyl indole RCS-4 (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone). We characterized the DNA-damaging properties of these drugs in different experimental systems. No evidence for induction of gene mutations was detected in bacterial (Salmonella/microsome) tests, but clear dose-dependent effects were found in in vitro single cell gel electrophoresis (SCGE) assays with human lymphocytes and with buccal- and lung-derived human cell lines (TR-146 and A-549). These experiments are based on the determination of DNA migration in an electric field and enable the detection of single- and double-strand breaks and apurinic sites. Furthermore, we found that both drugs induce micronuclei which are formed as a consequence of chromosomal aberrations. The lack of effects in SCGE experiments with lesion-specific enzymes (FPG, Endo III) shows that the DNA damage is not caused by formation of oxidatively damaged bases; experiments with liver enzyme homogenates and bovine serum albumin indicate that the drugs are not converted enzymatically to DNA-reactive intermediates. Furthermore, results with buccal- and lung-derived human cells show that gaseous treatment of the cells under conditions which reflect the exposure situation in drug users may cause damage of the genetic material in epithelia of the respiratory tract. Since DNA instability is involved in the etiology of cancer, these findings can be taken as an indication that consumption of the SCs may cause tumors in the respiratory tract of consumers.
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
authors: Franziska
authors: F
authors: Ferk
authors: Environmental Health Sciences and Hospital Infection Control, Medical Center, University of Freiburg, 79106, Freiburg, Germany.
authors: Richard
authors: R
authors: Gminski
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
authors: Halh
authors: H
authors: Al-Serori
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
authors: Miroslav
authors: M
authors: Mišík
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
authors: Armen
authors: A
authors: Nersesyan
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.
authors: Verena J
authors: VJ
authors: Koller
authors: Institute of Forensic Medicine, Medical Center, University of Freiburg, 79104, Freiburg, Germany.
authors: Verena
authors: V
authors: Angerer
authors: Institute of Forensic Medicine, Medical Center, University of Freiburg, 79104, Freiburg, Germany.
authors: Volker
authors: V
authors: Auwärter
authors: Environmental Health Sciences and Hospital Infection Control, Medical Center, University of Freiburg, 79106, Freiburg, Germany.
authors: Tao
authors: T
authors: Tang
authors: Environmental Health Sciences and Hospital Infection Control, Medical Center, University of Freiburg, 79106, Freiburg, Germany.|Institute of Earth and Environmental Science - Geochemistry, University of Freiburg, 79104, Freiburg, Germany.
authors: Ali Talib
authors: AT
authors: Arif
authors: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria. siegfried.knasmueller@meduniwien.ac.at.
authors: Siegfried
authors: S
authors: Knasmüller
mesh_terms: D000072283:A549 Cells; D001711:Biotransformation; D002186:Cannabinoids / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D015198:Designer Drugs / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D015162:Micronucleus Tests; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D065589:Respiratory Tract Absorption; D012142:Respiratory Tract Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: C000613875:2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone; D002186:Cannabinoids; D015198:Designer Drugs; D009153:Mutagens; C585106:XLR-11
keywords: Genotoxicity; Micronucleus assay; SCGE assay; Synthetic cannabinoids