Synthetic Cannabinoid Toxicity: Role of Biotransformation

合成大麻素毒性：生物转化的作用

• 批准号: 9914444
• 负责人: Paul L Prather
• 金额: $ 4.35万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914444
• 关键词: Acute; Adverse effects; Affinity; Agitation; Agonist; Auditory Hallucination; Binding; Biological; Biological Assay; Blood; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Chemicals; Chinese Hamster Ovary Cell; Chronic; Clinical; Complex Mixtures; Cytochrome P450; Dangerousness; Detection; Drug Exposure; Drug Kinetics; Drug abuse; Drug user; Enzymes; Formulation; Glucuronosyltransferase; Goals; Government regulations; Health; Hepatic; High Pressure Liquid Chromatography; Human; Hydroxylation; In Vitro; Individual; Injections; Intestines; K2/Spice; Kinetics; Legal; Life; Marijuana; Medical; Metabolic; Metabolic Biotransformation; Metabolism; Microsomes; Mus; Neuraxis; Parents; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Physiological; Plants; Powder dose form; Property; Protein Isoforms; Public Health; Reporting; Risk; Role; Safety; Sampling; Seizures; Smoke; Structure; Symptoms; Syncope; Tablets; Tachycardia; Teenagers; Testing; Tetrahydrocannabinol; Therapeutic; Time; Toxic effect; Urine; Visual Hallucination; acute toxicity; associated symptom; cannabimimetics; capsule; clinical effect; design; drug of abuse; experience; experimental study; in vivo; male; marijuana legalization; marijuana use; metabolic profile; nanomolar; public health relevance; receptor; sulfotransferase; synthetic cannabinoid

 DESCRIPTION (provided by applicant): The terms "K2" and "Spice" refer to any number of commercial products usually sold as "legal marijuana". These products contain dangerous synthetic cannabinoid (SCBs) that are presumed to possess psychoactive properties similar to ∆9-tetrahydrocannabinol (∆9-THC), the natural cannabinoid found in marijuana. ∆9-THC and SCBs both produce psychotropic actions by activating CB1 cannabinoid receptors (CB1Rs) in the CNS. However, SCBs are a chemically diverse group of compounds that are structurally distinct from ∆9-THC, and thus detection of their use is difficult and has led to widespread abuse. Medical use of marijuana and ∆9-THC has been shown to be safe. In marked contrast, no information is known concerning the safety or efficacy of any SCB found in K2, and reports suggest that many clinical effects of K2 products are distinct from those produced by marijuana and may present health risks. In this regard, our preliminary analysis of urine samples from SCB users by LC-MS/MS suggests that levels of SCB metabolites correlate with clinical symptoms that may be life threatening. Furthermore, we reported that several hydroxylated metabolites of SCBs retain high affinity and activity at CB1R and CB2Rs, and dramatically increase acute effects of parent SCBs. Therefore, in an individual user, the physiological effects of SCBs may represent an "entourage" effect caused 1) by the distinct blend of SCBs in a given product, and 2) further influenced by the individual's metabolic capacity to transform SCBs into distinct Phase I and II active metabolites. Thus, it is important to define the metabolic profile of SCBs in humans and their biological activity at CB1Rs and CB2Rs. The goal of this project is to elucidate the biodisposition, biotransformation, and biological activity of SCBs and their metabolites at CB1Rs and CB2Rs in humans, and correlate these findings with acute and chronic adverse effects in mice. We will test the hypothesis that in vivo hydroxylation of SCBs by cytochromes P450 (CYPs) and subsequent conjugation by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) produces a complex mixture of high affinity CB1R and CB2R agonists, antagonists, and inverse agonists. These metabolites acting "in concert" with parent SCBs produce the distinct pharmacologic effects and toxicity of SCBs in humans. Our interdisciplinary team will explore this hypothesis by four Specific Aims. Aim 1 will employ LC-MS/MS to identify in human urine the primary and secondary metabolites of 9 high priority SCBs abused in K2 products. Clinical symptom profiles will also be collected for each patient. Experiments in Aim 2 will characterize the human Phase I and II enzymes responsible for the in vitro metabolism of SCBs. In Aim 3, SCBs and their metabolites will be examined for the ability to bind to and activate human CB1Rs and CB2Rs. Finally, studies in Aim 4 will determine the pharmacokinetic profile of SCBs and determine if these compounds and their metabolites elicit cannabimimetic effects in mice. This collaborative translational project will provide information concerning the metabolism, pharmacology and toxicology of SCBs to identify likely health risks to the public.

 描述（由适用提供）：“ K2”和“ SPICE”一词是指通常以“法律大麻”出售的任何数量的商业产品。这些产品含有危险的合成大麻素（SCB），其具有类似于大麻中发现的天然大麻素的精神活性特性（Δ9-四氢大麻酚（∆9-THC））。 ∆9-THC和SCB都通过激活CNS中的CB1大麻素受体（CB1R）来产生精神作用。但是，SCB是一种化学多样的化合物，在结构上与∆9-THC不同，因此很难检测其使用，并导致广泛滥用。大麻和∆9-THC的医疗用途已被证明是安全的。与之形成鲜明对比的是，尚无有关K2中任何SCB的安全性或有效性的信息，并且报告表明，K2产品的许多临床作用与大麻产生的临床作用不同，并且可能带来健康风险。在这方面，我们对LC-MS/MS对SCB使用者的尿液样本的初步分析表明，SCB代谢物水平与可能威胁生命的临床症状相关。此外，我们报道说，SCB的几种羟化代谢产物保留了CB1R和CB2RS的高亲和力和活性，并大大增加了父型SCB的急性效应。因此，在单个用户中，SCB的物理效应可能代表“随行人员”效应1）由给定产品中的SCB的独特融合而造成的，以及2）进一步受个人的代谢能力，将SCB转化为I阶段I和II期有效代谢物的代谢能力。这是重要的是要定义人类中SCB的代谢谱及其在CB1RS和CB2RS上的生物学活性。该项目的目的是阐明SCB及其在人类CB1RS和CB2RS上的SCB及其代谢产物的生物脱位，生物转化和生物学活性，并将这些发现与小鼠中的急性和慢性不良作用相关联。我们将测试以下假设：细胞色素p450（CYPS）对SCB的体内羟基化以及随后通过UDP-葡萄糖醛糖基转移酶（UGTS）和磺胺转移酶（SULTS）（SULTS）的结合，从而产生高亲和力CB1R和CB1R和CB2RIST的高度混合物和CB2RISTISS和CB2RISTS，INSISTS，INSISTS，INSISTS，INSISTS，INSISTS，INSISTS，INSISTING INS INSISTING INSIST and INSIST and sCB。这些代谢物与父型SCB的作用“协调一致”产生了SCB在人类中的独特药物作用和毒性。我们的跨学科团队将以四个具体目标探讨这一假设。 AIM 1将采用LC-MS/MS在人类尿液中识别9个高优先级SCB的主要和次级代谢产物中滥用了K2产品。还将为每个患者收集临床症状特征。 AIM 2中的实验将表征人类I期和II期酶，负责SCB的体外代谢。在AIM 3中，将检查SCB及其代谢产物的代谢物，以结合和激活人CB1R和CB2RS。最后，在AIM 4中的研究将确定SCB的药代动力学特征，并确定这些化合物及其代谢物是否在小鼠中引起大麻含量。该协作转化项目将提供有关SCB的新陈代谢，药理学和毒理学的信息，以确定可能对公众的健康风险。