Institute of Cancer Research, Department of Internal Medicine 1, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna, Austria.
Institute of Forensic Medicine, University Medical Center Freiburg, Albertstraße 9, 79104 Freiburg, Germany.
Toxicol Appl Pharmacol. 2014 Jun 1;277(2):164-71. doi: 10.1016/j.taap.2014.03.014. Epub 2014 Mar 28.
Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of "Spice" and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.
大麻环已醇（CP-47,497-C8）是一组拟大麻环已基苯酚的代表物，自 2008 年以来，它被添加到草药混合物中作为大麻的替代品。虽然在开始时 CP-47,497-C8 是“香料”和类似产品的主要成分，但它部分被氨基烷基吲哚型大麻素受体激动剂如 JWH-018、JWH-073 或 JWH-250 取代，但从未完全从市场上消失。由于关于其毒理学性质的信息很少，我们研究了该药物在人类来源的细胞系中的作用。在口腔衍生（TR146）和肝衍生（HepG2）细胞系中，通过一系列测定（SRB、XTT、LDHe 和 NR 试验）研究了细胞毒性作用。在两种前一种测定中，在≥7.5 μM 的水平上观察到最强的作用，表明该化合物干扰蛋白质合成并导致膜损伤。在额外的彗星试验中，在≥10 μM 的水平上检测到 DNA 损伤。用损伤特异性酶的实验表明，这些作用不是由于 DNA 碱基的氧化损伤引起的。沙门氏菌/微粒体试验中的阴性结果和细胞系中的微核试验的阳性结果表明，该化合物不会引起基因突变，而是作用于染色体水平。与其他合成大麻素不同，在骨髓衍生的 U2-OS 细胞中的荧光素酶试验中没有显示出雌激素/抗雌激素性质的迹象。总之，我们的研究结果表明，该药物只有较弱的细胞毒性作用。然而，染色体损伤的诱导表明，由于其对遗传物质稳定性的影响，它可能会对使用者造成不良影响。
