title: Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB₁.
abstract: Products containing synthetic cannabinoids are consumed as a surrogate for marihuana due to their non-detectability with commonly used drug tests and their strong cannabimimetic effects. Because data concerning their toxicological properties are scarce, the cytotoxic, genotoxic, immunomodulatory, and hormonal activities of four naphthoylindole compounds (JWH-018, JWH-073, JWH-122 and JWH-210) and of one benzoylindole (AM-694) were studied in human cell lines and primary cells; tetrahydrocannabinol was included as the classical non-endogenous cannabinoid receptor ligand. All compounds induced damage to the cell membranes of buccal (TR146) and breast (MCF-7) derived cells at concentrations of ≥75-100 μM. No cytotoxic responses were seen in other assays which reflect mitochondrial damage, protein synthesis, and lysosomal activities. JWH-073 and JWH-122 induced DNA migration in buccal and liver cells (HepG2) in single cell gel electrophoresis assays, while JWH-210 was only in the latter cell line active. No estrogenic activities were detected in bone marrow cells (U2-OS), but all compounds caused anti-estrogenic effects at levels between 2.1 and 23.0 μM. Furthermore, no impact on cytokine release (i.e., on IL-10, IL-6, IL-12/23p40 and TNFα levels) was seen in LPS-stimulated human PBMCs, except with JWH-210 and JWH-122 which caused a decrease of TNFα and IL-12/23p40. All toxic effects were observed with concentrations higher than those expected in body fluids of users. Since genotoxic effects are in general linear over a wide concentration range and the exposure levels may be higher in epithelial cells than [corrected] in serum, further experimental work is required to find out if DNA damage takes place in drug users.
authors.affiliation: Department of Internal Medicine 1, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna, Austria.
authors.forename: Verena J
authors.initials: VJ
authors.lastname: Koller
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
authors.forename: Volker
authors.initials: V
authors.lastname: Auwärter
authors.forename: Sabine
authors.initials: S
authors.lastname: Fuchs
authors.forename: Siegfried
authors.initials: S
authors.lastname: Knasmueller
mesh_terms: D002186:Cannabinoids / Q000378:metabolism / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D020552:Comet Assay; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D007211:Indoles / Q000633:toxicity; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D061986:MCF-7 Cells; D009281:Naphthalenes / Q000633:toxicity; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C582338:4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone; C568441:AM 694; D002186:Cannabinoids; D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D011960:Receptors, Estrogen; C568258:JWH-073; C552597:1-pentyl-3-(1-naphthoyl)indole