Impact of E-Cigarette Liquid Flavoring Agents on Activity of Microsomal Recombinant CYP2A6, the Primary Nicotine-Metabolizing Enzyme
Impact of E-Cigarette Liquid Flavoring Agents on Activity of Microsomal Recombinant CYP2A6, the Primary Nicotine-Metabolizing Enzyme
复制标题
DOI：
10.1021/acs.chemrestox.9b00514
复制
发表时间：
2020-07-20
影响因子：
4.1
通讯作者：
Madden, Michael C.
中科院分区：
文献类型：
--
作者：
Winters, Brett R.;Kochar, Tavleen K.;Madden, Michael C.
尼古丁是传统香烟和电子香烟中主要的精神活性化学物质。传统香烟和电子烟中的尼古丁含量是公共卫生的一个重要问题。使用电子烟导致的尼古丁暴露很重要，主要是因为尼古丁具有成瘾性，但也有人担心电子烟使用者会出现尼古丁中毒。电子液体中的尼古丁浓度差异很大。此外，由于 CYP2A6（负责代谢约 80% 尼古丁的酶）的多态性，尼古丁代谢率存在显着的遗传变异。最近的研究表明，芳香醛也会降低 CYP2A6 的活性，例如作为调味剂添加到电子烟油中的芳香醛，这可能会增加尼古丁血清浓度。然而，调味电子烟油对 CYP2A6 活性的影响尚不清楚。在这项研究中，我们研究了三种调味电子烟油对微粒体重组 CYP2A6 的影响。微粒体重组 CYP2A6 在浓度高达 0.125% (v/v) 的电子烟液中受到攻击，并使用探针分子方法监测代谢活性。两种电子烟液表现出对 CYP2A6 活性的剂量依赖性抑制。通过质谱分析来鉴定调味电子烟液中抑制 CYP2A6 的调味剂。随后将微粒体重组CYP2A6暴露于浓度范围为0.03μM至500μM的调味剂中。肉桂醛和苯甲醛被发现是所测试调味剂中微粒体CYP2A6最有效的抑制剂，确定的IC50值分别为1.1μM和3.0μM。这些数据表明某些芳香醛调味剂是 CYP2A6 的有效抑制剂，可能会减少体内的尼古丁代谢。这些发现表明迫切需要评估电子烟液中调味剂对尼古丁体内药代动力学的影响。
Nicotine is the primary psychoactive chemical in both traditional and electronic cigarettes (e-cigarettes). Nicotine levels in both traditional cigarettes and e-cigarettes are an important concern for public health. Nicotine exposure due to e-cigarette use is of importance primarily due to the addictive potential of nicotine, but there is also concern for nicotine poisoning in e-cigarette users. Nicotine concentrations in e-liquids vary widely. Additionally, there is significant genetic variability in the rate of metabolism of nicotine due to polymorphisms of CYP2A6, the enzyme responsible for the metabolism of approximately 80% of nicotine. Recent studies have shown CYP2A6 activity is also reduced by aromatic aldehydes such as those added to e-liquids as flavoring agents, which may increase nicotine serum concentrations. However, the impacts of flavored e-liquids on CYP2A6 activity are unknown. In this study, we investigated the impact of three flavored e-liquids on microsomal recombinant CYP2A6. Microsomal recombinant CYP2A6 was challenged at e-liquid concentrations ranging up to 0.125% (v/v) and monitored for metabolic activity using a probe molecule approach. Two e-liquids exhibited dose-dependent inhibition of CYP2A6 activity. Mass spectrometry was conducted to identify flavoring agents in flavored e-liquids that inhibited CYP2A6. Microsomal recombinant CYP2A6 was subsequently exposed to flavoring agents at concentrations ranging from 0.03 mu M to 500 mu M. Cinnamaldehyde and benzaldehyde were found to be the most potent inhibitors of microsomal CYP2A6 of the flavoring agents tested, with identified IC50 values of 1.1 mu M and 3.0 mu M respectively. These data indicate certain aromatic aldehyde flavoring agents are potent inhibitors of CYP2A6, which may reduce nicotine metabolism in vivo. These findings indicate an urgent need to evaluate the effects of flavoring agents in e-cigarette liquids on the pharmacokinetics of nicotine in vivo.