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（由申请人提供）：术语“K2”和“香料”是指通常作为“合法大麻”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），被认为具有与 Δ 类似的精神活性特性。 9-四氢大麻酚 (Δ9-THC) 是大麻中发现的天然大麻素，Δ9-THC 和 SCB 均通过激活 CB1 大麻素产生精神作用。然而，SCB 是一组化学性质多样的化合物，其结构与 Δ9-THC 不同，因此很难检测到它们的使用，并导致大麻和 Δ9 的广泛滥用。 - THC 已被证明是安全的，与此形成鲜明对比的是，目前尚无关于 K2 中发现的任何 SCB 的安全性或功效的信息，并且报告表明 K2 产品的许多临床效果与大麻产生的效果不同，可能会带来健康问题。在这方面，我们通过 LC-MS/MS 对 SCB 使用者的尿液样本进行的初步分析表明，SCB 代谢物的水平与可能危及生命的临床症状相关。此外，我们报道了 SCB 的几种羟基化代谢物保留了高亲和力。 CB1R 和 CB2R 的活性，并显着增加亲代 SCB 的急性效应，因此，在个体使用者中，SCB 的生理效应可能代表 1) 由不同混合物引起的“随从”效应。给定产品中的 SCB，以及 2) 受个体将 SCB 转化为不同的 I 期和 II 期活性代谢物的代谢能力的影响。因此，定义 SCB 在更多人类中的代谢特征及其在 CB1R 和 CB2R 上的生物活性非常重要。该项目的目标是阐明 SCB 及其代谢物在人类 CB1R 和 CB2R 中的生物处置、生物转化和生物活性，并将这些发现与小鼠的急性和慢性不良反应相关联，我们将测试细胞色素 P450 (CYP) 体内 SCB 的羟基化以及随后 UDP-葡萄糖醛酸基转移酶 (UGT) 和磺基转移酶 (SULT) 的结合产生复杂的混合物的假设。高亲和力 CB1R 和 CB2R 激动剂、拮抗剂和反向激动剂这些代谢物“协同”作用。我们的跨学科团队将通过四个具体目标探索这一假设，目标 1 将采用 LC-MS/MS 来鉴定人尿液中 9 种高优先级代谢物。目标 2 中的实验还将收集 K2 产品中滥用的 SCB，以表征目标 3 中负责 SCB 体外代谢的人类 I 期和 II 期酶。最后，Aim 4 中的研究将检查 SCB 及其代谢物结合并激活人类 CB1R 和 CB2R 的能力，并确定这些化合物及其代谢物是否在小鼠中引起大麻模拟作用。该项目将提供有关 SCB 的代谢、药理学和毒理学的信息，以确定可能对公众造成的健康风险。