CYP2A6 inhibitors derived from literature with the respective reported assay results and references

Tobacco smoking has been highlighted as a major health challenge in modern societies. Despite not causing death directly, smoking has been associated with several health issues, such as cardiovascular diseases, respiratory disorders, and several cancer types. Moreover, exposure to nicotine during pregnancy has been associated with adverse neurological disorders in babies. Nicotine Replacement Therapy (NRT) is the most common strategy employed for smoking cessation, but despite its widespread use, NRT presents with low success and adherence rates. This is attributed partially to the rate of nicotine metabolism by cytochrome P450 2A6 (CYP2A6) in each individual. Nicotine addiction is correlated with the high rate of its metabolism, and thus, novel strategies need to be implemented in NRT protocols. Naturally derived products are a cost-efficient and rich source for potential inhibitors, with the main advantages being their abundance and ease of isolation. This systematic review aims to summarize the natural products that have been identified as CYP2A6 inhibitors, validated through in vitro and/or in vivo assays, and could be implemented as nicotine metabolism inhibitors. The scope is to present the different compounds and highlight their possible implementation in NRT strategies. Additionally, this information would provide valuable insight regarding CYP2A6 inhibitors, that can be utilized in drug development via the use of in silico methodologies and machine-learning models to identify new potential lead compounds for optimization and implementation in NRT regimes.吸烟已被视作现代社会面临的重大公共健康挑战。尽管吸烟不会直接致人死亡，但与心血管疾病、呼吸系统病症以及多种癌症等多种健康问题密切相关。此外，孕期接触尼古丁还与婴儿出现不良神经系统疾病存在显著关联。尼古丁替代疗法（Nicotine Replacement Therapy, NRT）是目前最为常用的戒烟策略，尽管该疗法应用广泛，但其成功率与患者依从性均偏低。这一现象的部分诱因在于，不同个体体内细胞色素P450 2A6（cytochrome P450 2A6, CYP2A6）对尼古丁的代谢速率存在差异。尼古丁成瘾与其代谢速率呈正相关，因此亟需对尼古丁替代疗法的方案进行优化，引入全新的干预策略。天然来源产物是潜在代谢抑制剂的低成本、高丰度来源，其核心优势在于资源充裕且易于分离纯化。本系统综述旨在汇总已被鉴定为CYP2A6抑制剂的天然产物——这些抑制剂均通过体外（in vitro）和/或体内（in vivo）实验验证，可作为尼古丁代谢抑制剂应用于戒烟治疗。本综述的目标在于梳理各类相关化合物，并阐明其在尼古丁替代疗法策略中的潜在应用价值。此外，本研究所得数据可为CYP2A6抑制剂的相关研究提供宝贵参考，可借助虚拟（in silico）研究方法与机器学习模型开展药物开发工作，以识别全新的潜在先导化合物，用于优化并应用于尼古丁替代疗法方案中。