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.

Focus on cannabinoids and synthetic cannabinoids

“…Hyperventilation or apnea, pneumonia, alveolar infiltrates are reported in case series . Ferk et al . showed that in human lung and buccal cell lines, DNA damage occurs from SCs exposure (XRL‐11 and RCS‐4 in this study).…”

“…Hyperventilation or apnea, pneumonia, alveolar infiltrates are reported in case series. 60 Ferk et al 61 showed that in human lung and buccal cell lines, DNA damage occurs from SCs exposure (XRL-11 and RCS-4 in this study). This indicates that SCs may be directly genotoxic to lung epithelium cells, independently of tobacco and/or pyrogens brought on by smoking practices.…”

“…Nevertheless, considering the more highly potent CB1R activity and shorter time to effect, SCs could carry a major risk of dependence. To support this, in a New Zealand detoxification center, 41 out of a total of 47 patients spoke of difficulties in stopping SCs use due to the development of withdrawal symptoms . These included anxiety, mood swings, nausea, and loss of appetite.…”

Cytotoxic and genotoxic responses of human lung cells to combustion smoke particles of Miscanthus straw, softwood and beech wood chips

“…To detect DNA damage by PM 0.4–1 emission, the comet assay was carried out according to the protocols of (Tice et al, 2000; Ferk et al, 2016), with minor modifications. The BEAS-2B cells were washed extensively with 1x PBS buffer (Ca-Mg-free; pH = 7.3; 20 °C; Gibco Life Technologies, Karlsruhe, Germany).…”

The ongoing challenge of novel psychoactive drugs of abuse. Part I. Synthetic cannabinoids (IUPAC Technical Report)

“…Some adverse effects experienced by SC consumers include, but are not limited to, tachycardia, anxiety, hallucinations, suicidal thoughts, acute kidney injury and hepatotoxicity, convulsions, psychosis, and death [14,55]. Studies revealed that some SCs induced chromosomal damage in in vitro studies [56,57], suggesting a tumor risk in chronic consumers. Cannabinoid-specific therapeutic tools are not available for the clinical management of patients, which instead relies on reducing the severe symptoms of an individual [58].…”