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Outline
In recent years, the synthetic cannabinoid N-(1-amino-3, 3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3-carboxamide (ADB-BUTINACA) has attracted widespread attention due to its high affinity for the CB1 receptor and associated abuse risk; however, its toxicity mechanism remains poorly understood. This study aimed to systematically investigate the toxicological mechanisms of ADB-BUTINACA using an integrated approach. We established an acute rat exposure model (low and high doses: 0.1 and 1 mg·kg-1) and employed untargeted metabolomics combined with molecular docking analysis to examine its effects on the urinary metabolome and toxicity pathways. Our analysis identified 52 significantly altered metabolites, including taurine and phenylacetaldehyde, and revealed six disturbed metabolic pathways, such as phenylalanine metabolism and one-carbon metabolism. Notably, choline and methionine were pinpointed as potential dose-dependent biomarkers. Molecular docking results demonstrated a strong binding affinity (-7.8 kcal·mol-1) between ADB-BUTINACA and aldehyde dehydrogenase ALDH3, suggesting that the compound inhibits ALDH3 activity. This inhibition likely disrupts phenylalanine metabolism, leading to the accumulation of phenylacetaldehyde and the upregulation of phenylacetylglycine, thereby inducing oxidative stress and potential cardiovascular and neurotoxicity. Concurrently, the downregulation of methionine and choline indicated an impairment of one-carbon metabolism, which may further exacerbate oxidative stress. In conclusion, this study elucidates the mechanism by which ADB-BUTINACA exposure induces oxidative stress primarily through disrupting phenylalanine and one-carbon metabolism, utilizing non-targeted metabolomics and molecular docking. The identified biomarkers provide a crucial theoretical foundation for future research on the toxicity mechanisms, clinical detection, and risk assessment of synthetic cannabinoids. The experimental protocol complied with the welfare and ethical requirements for experimental animals and was approved by the Animal Ethics Committee of Zhejiang Chinese Medical University (Approval number: 20220718-11).
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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