Brain CYP2B induction can decrease nicotine levels in the brain.
Brain CYP2B induction can decrease nicotine levels in the brain.
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DOI：
10.1111/adb.12411
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发表时间：
2017-09
影响因子：
3.4
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
Garcia KLP;Lê AD;Tyndale RF
尼古丁可被CYP2B酶代谢；在接受尼古丁治疗的大鼠和猴子以及人类吸烟者中，CYP2B的含量更高。7天的尼古丁处理增加了大鼠大脑中CYP2B的表达，但没有增加肝脏中CYP2B的表达，并降低了对CYP2B底物异丙酚的行为反应和大脑水平（离体）。然而，CYP2B诱导对体内循环脑尼古丁的时间过程和水平的影响尚未得到证实。使用脑微透析，在第一天和7天尼古丁治疗后测量皮下尼古丁注射后的尼古丁水平。时间与治疗之间存在显著的交互作用（p = 0.01）；治疗后尼古丁峰值水平（注射后15-45分钟）较低（p = 0.04），与CYP2B诱导一致。在两周的洗脱期后，脑尼古丁水平上升到第一天的水平（p = 0.02），与脑CYP2B水平恢复到基线一致。经脑前处理的CYP2B抑制剂c8 -黄药可使脑内尼古丁水平急剧升高，并在尼古丁治疗7天后升高，说明脑内尼古丁水平的改变是由于脑内CYP2B活性的改变。血浆尼古丁水平在任何时间或治疗取样中都没有改变，证实对周围尼古丁代谢没有影响。这些结果表明，慢性尼古丁通过增加大脑CYP2B活性，降低大脑尼古丁水平，从而改变尼古丁的强化作用。吸烟者大脑中较高的CYP2B水平可以降低大脑中的尼古丁水平；由于这种诱导会在持续接触尼古丁后发生，它可能会增加戒断症状，并有助于维持吸烟行为。
Nicotine can be metabolized by the enzyme CYP2B; brain CYP2B is higher in rats and monkeys treated with nicotine, and in human smokers. A 7-day nicotine treatment increased CYP2B expression in rat brain but not liver, and decreased the behavioral response and brain levels (ex vivo) to the CYP2B substrate propofol. However, the effect of CYP2B induction on the time course and levels of circulating brain nicotine in vivo has not been demonstrated. Using brain microdialysis, nicotine levels following a subcutaneous nicotine injection were measured on day one and after a 7-day nicotine treatment. There was a significant time x treatment interaction (p = 0.01); peak nicotine levels (15–45 minutes post-injection) were lower after treatment (p = 0.04) consistent with CYP2B induction. Following a two-week washout period, brain nicotine levels increased to day one levels (p = 0.02), consistent with brain CYP2B levels returning to baseline. Brain pretreatment of the CYP2B inhibitor, C8-xanthate, increased brain nicotine levels acutely and after 7-day nicotine treatment, indicating the alterations in brain nicotine levels were due to changes in brain CYP2B activity. Plasma nicotine levels were not altered for any time or treatment sampled, confirming no effect on peripheral nicotine metabolism. These results demonstrate that chronic nicotine, by increasing brain CYP2B activity, reduces brain nicotine levels, which could alter nicotine’s reinforcing effects. Higher brain CYP2B levels in smokers could lower brain nicotine levels; as this induction would occur following continued nicotine exposure it could increase withdrawal symptoms and contribute to sustaining smoking behavior.
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影响因子：
3.4
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