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Reduced CYP2B6 metabolism influences smoking initiation and treatment response: i

CYP2B6 代谢减少会影响吸烟开始和治疗反应：i

基本信息

批准号：
8113281
负责人：
RACHEL Fynvola TYNDALE
金额：
$ 13.48万
依托单位：
CENTRE FOR ADDICTION AND MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113281
关键词：
Abstinence Adolescent Adult Affect Affective Behavior Brain Brain region Bupropion CYP2B1 gene CYP2B6 gene Cerebral Ventricles Cessation of life Chemicals Consumption Cytochrome P450 Data Development Drug Addiction Drug abuse Enzymes Exposure to Family Study Genetic Health Homologous Gene Human Human Genetics Injection of therapeutic agent Investigation Knowledge Lead Mediating Metabolism Methodology Modeling Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Pharmaceutical Preparations Placebos Population Prevention strategy Procedures Psychological reinforcement Rattus Relapse Research Risk Role Self Administration Severities Smoke Smoker Smoking Smoking Behavior Smoking Prevention Techniques Testing Twin Studies Variant Withdrawal Withdrawal Symptom attenuation base craving enzyme activity experience follow-up genetic variant human CYP2B6 protein improved inhibitor/antagonist neuroadaptation neurochemistry nornicotine novel novel strategies open label public health relevance response smoking cessation success treatment response treatment strategy varenicline

项目摘要

DESCRIPTION (provided by applicant): About 21% of US adults are current smokers and smoking rates have not declined in recent years. Smoking causes about 3 million deaths a year world-wide, and while roughly 80% of smokers desire to quit smoking, most fail. Because of continued smoking acquisition and low long term abstinence rates, smoking remains a significant health problem. This project aims to gain a better understanding of the mechanisms behind the variation between people in their risk for acquisition of smoking and their success in smoking cessation and to develop better prevention strategies and treatments. Family and twin studies illustrate an underlying genetic component to many aspects of smoking, and people with genetic variants of the drug metabolizing enzyme CYP2B6, that result in reduced enzyme (slow CYP2B6 metabolizers), are at greater risk for becoming nicotine-dependent, and upon stopping smoking, experience more craving and withdrawal; they have lower quit rates but respond better to the cessation drugs bupropion and varenicline. CYP2B6 is unlikely to contribute to overall nicotine metabolism, but is present in the brain where it can contribute to local metabolism of endogenous compounds, and to the brain levels of nicotine and its metabolites, such as nornicotine. This proposal will investigate the role of reduced brain CYP2B6 in the differences in smoking- related behaviors between CYP2B6 slow and normal metabolizers. A novel procedure will be used in rats to model reduced brain CYP2B6 metabolism in human CYP2B6 slow metabolizers, wherein a specific mechanism-based chemical inhibitor will be injected directly into rat brain cerebral ventricles. This procedure will be used in combination with a rat nicotine self-administration paradigm to investigate the role of reduced brain CYP2B6 metabolism in the increased rate and risk of becoming nicotine dependent. The rate of acquisition of nicotine self-administration by rats should be higher with inhibition of brain CYP2B, as there should be higher nicotine levels in the brain than without inhibition, increasing nicotine's reinforcement. This brain CYP inhibition procedure will also be used in combination with a rat model of nicotine withdrawal to investigate the role of reduced brain CYP2B6 metabolism in severity of withdrawal from smoking, and in the response to bupropion and varenicline. With brain CYP2B inhibition, the rats should experience increased withdrawal symptoms upon cessation of nicotine treatment, due to increased brain exposure to nicotine and reduced nornicotine levels while receiving nicotine. Similarly, these rats should experience greater attenuation of withdrawal symptoms with bupropion and varenicline. The results of this project may lead to further investigation of the role of brain CYPs in drug abuse and addiction, and to novel approaches for development of better treatment strategies for smoking cessation. The field of brain CYP-mediated enzyme metabolism is highly unique; examining manipulation of brain CYP-mediated metabolism is novel and represents an exciting new avenue of research. PUBLIC HEALTH RELEVANCE: About 21% of US adults are smokers and smoking causes about 3 million deaths a year world-wide. Smoking rates have not declined in recent years in the US indicating many people are still becoming smokers and only some are able to stop smoking. This project takes a novel approach to understanding the mechanisms whereby some people are more vulnerable to both becoming and remaining smokers, and whereby some smokers respond better to cessation drugs than others. Ultimately these studies may be useful in developing better smoking prevention strategies and treatments.

描述(申请人提供)：大约21%的美国成年人是目前的吸烟者，吸烟率近年来没有下降。吸烟每年导致全球约300万人死亡，虽然大约80%的吸烟者希望戒烟，但大多数人都失败了。由于持续吸烟和长期戒烟率低，吸烟仍然是一个重大的健康问题。该项目旨在更好地了解人们获得吸烟风险和成功戒烟之间的差异背后的机制，并制定更好的预防策略和治疗方法。家庭和双胞胎研究表明，吸烟的许多方面都有潜在的遗传因素，携带药物代谢酶CYP2B6基因变异的人，会导致酶(缓慢的CYP2B6代谢物)减少，变得对尼古丁依赖的风险更大，在戒烟后，他们会经历更多的渴望和戒烟；他们戒烟率较低，但对戒烟药物安非他酮和varenicline的反应更好。CYP2B6不太可能对尼古丁的整体代谢做出贡献，但存在于大脑中，在那里它可以促进内源性化合物的局部代谢，并有助于大脑中尼古丁及其代谢物的水平，如去甲尼古丁。这项建议将调查大脑中减少的CYP2B6在慢代谢者和正常代谢者吸烟相关行为差异中的作用。一种新的方法将在大鼠身上用人的CYP2B6慢代谢物建立脑内CYP2B6代谢减少的模型，其中基于特定机制的化学抑制剂将直接注入大鼠脑室。这一过程将与大鼠尼古丁自我给药范例结合使用，以调查大脑中CYP2B6代谢减少在尼古丁依赖增加的比率和风险中所起的作用。大鼠自我给予尼古丁的速率应该更高，因为大脑中应该有比没有抑制的更高的尼古丁水平，从而增加尼古丁的强化。这种大脑细胞色素P450抑制程序也将与尼古丁戒断的大鼠模型结合使用，以研究大脑细胞色素P450代谢降低在戒烟严重程度以及对安非他酮和伐伦克林的反应中所起的作用。由于大脑对CYP2B的抑制，大鼠在停止尼古丁治疗后应该会经历更多的戒断症状，这是因为在接受尼古丁治疗时，大脑暴露于尼古丁的增加和去甲尼古丁水平的降低。同样，使用安非他酮和伐伦克林，这些大鼠应该会经历更大程度的戒断症状的缓解。该项目的结果可能会导致进一步研究大脑中的Cyps在药物滥用和成瘾中的作用，并为开发更好的戒烟治疗策略提供新的方法。脑细胞色素P450介导的酶代谢领域是非常独特的；研究脑细胞色素P450介导的代谢的操作是新颖的，代表了一条令人兴奋的新的研究途径。与公共健康相关：大约21%的美国成年人是吸烟者，全球每年约有300万人死于吸烟。近年来，美国的吸烟率并没有下降，这表明许多人仍在成为吸烟者，只有一部分人能够戒烟。这个项目采用了一种新的方法来理解一些人更容易成为吸烟者和继续吸烟者，以及一些吸烟者对戒烟药物的反应比其他人更好的机制。最终，这些研究可能有助于开发更好的吸烟预防策略和治疗方法。