Inhibitory effects of neurotransmitters and steroids on human CYP2A6
Inhibitory effects of neurotransmitters and steroids on human CYP2A6
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DOI：
10.1124/dmd.106.014084
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发表时间：
2007-04-01
影响因子：
3.9
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Higashi, Eriko;Nakajima, Miki;Yokoi, Tsuyoshi
人CYP 2A 6催化尼古丁、可替宁和香豆素以及一些药物的代谢。CYP 2A 6在肝脏、脑和类固醇相关组织中高度表达。在这项研究中，我们研究了神经递质和类固醇激素对CYP 2A 6活性的抑制作用。我们发现，在杆状病毒感染的昆虫细胞中表达的重组CYP 2A 6对香豆素7-羟基化和可替宁3 '-羟基化的作用受到色胺（Ki = 0.2 μ M）、血清素（Ki = 252 μ M和167 μ M）、多巴胺（Ki = 49 μ M和22 μ M）和组胺（Ki = 428 μ M和359 μ M）的竞争性抑制。尼古丁形成可替宁受到色胺（Ki = 0.7 μ M，竞争性）、血清素（Ki = 272 μ M，非竞争性）、多巴胺、去甲肾上腺素和肾上腺素（Ki = 11 μ M、54 μ M和81 μ M，非竞争性）的抑制。雌激素（Ki = 0.6 - 3.8 μ M）、雄激素（Ki = 60-149 μ M）和皮质酮（Ki = 36 μ M）也抑制可替宁的形成，但香豆素7-羟基化和可替宁3 '-羟基化不抑制。尼古丁-δ（5 '（1'））-亚胺鎓离子从尼古丁形成不受这些类固醇激素的影响，表明可替宁形成的抑制是由于对醛氧化酶的抑制作用。烟碱-δ（5 ′（1 ′））-亚胺鎓离子的形成被色胺（Ki = 0.3 μ M）、血清素（Ki = 316 μ M）、多巴胺（Ki = 66 μ M）和组胺（Ki = 209 μ M）竞争性抑制。因此，我们发现一些神经递质抑制CYP 2A 6活性，与CYP 2A 6依赖性代谢的个体间和个体内差异有关。类固醇激素对醛氧化酶的抑制作用也可能导致尼古丁代谢的个体差异。
Human CYP2A6 catalyzes the metabolism of nicotine, cotinine, and coumarin as well as some pharmaceutical drugs. CYP2A6 is highly expressed in liver and, also, in brain and steroid-related tissues. In this study, we investigated the inhibitory effects of neurotransmitters and steroid hormones on CYP2A6 activity. We found that coumarin 7-hydroxylation and cotinine 3'-hydroxylation by recombinant CYP2A6 expressed in baculovirus-infected insect cells were competitively inhibited by tryptamine ( both K-i = 0.2 mu M), serotonin (K-i = 252 mu M and 167 mu M), dopamine (K-i = 49 mu M and 22 mu M), and histamine (K-i = 428 mu M and 359 mu M). Cotinine formation from nicotine was inhibited by tryptamine ( K-i = 0.7 mu M, competitive), serotonin (K-i = 272 mu M, noncompetitive), dopamine, noradrenaline, and adrenaline (K-i = 11 mu M, 54 mu M, and 81 mu M, uncompetitive). Estrogens ( K-i = 0.6 - 3.8 mu M), androgens ( K-i = 60-149 M), and corticosterone ( K-i = 36 mu M) also inhibited cotinine formation, but coumarin 7-hydroxylation and cotinine 3'-hydroxylation did not. Nicotine-Delta(5'(1'))- iminium ion formation from nicotine was not affected by these steroid hormones, indicating that the inhibition of cotinine formation was due to the inhibitory effects on aldehyde oxidase. The nicotine-Delta(5'(1'))-iminium ion formation was competitively inhibited by tryptamine ( K-i = 0.3 mu M), serotonin ( K-i = 316 mu M), dopamine ( K-i = 66 mu M), and histamine ( K-i = 209 mu M). Thus, we found that some neurotransmitters inhibit CYP2A6 activity, being related with inter- and intraindividual differences in CYP2A6-dependent metabolism. The inhibitory effects of steroid hormones on aldehyde oxidase may also contribute to interindividual differences in nicotine metabolism.