Synthetic Cannabinoid Toxicity: Role of Biotransformation

合成大麻素毒性：生物转化的作用

• 批准号: 9037178
• 负责人: Paul L Prather
• 金额: $ 54.97万
• 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/9037178
• 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; 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; Injection of therapeutic agent; Intestines; K2/Spice; Kinetics; Legal; Life; Marijuana; Marketing; Medical; Metabolic; Metabolic Biotransformation; Metabolism; Microsomes; Mus; Neuraxis; Parents; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Physiological; Plants; Powder dose form; Property; Protein Isoforms; Public Health; Recombinants; Reporting; Risk; Role; Safety; Sampling; Seizures; Serum; Smoke; 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; in vivo; male; marijuana legalization; marijuana use; metabolic profile; nanomolar; public health relevance; receptor; research study; 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“法律的大麻”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（SCBs），被认为具有类似于大麻中发现的天然大麻素- 109-THC和SCBs都通过激活CNS中的CB 1大麻素受体（CB 1 R）产生精神作用。然而，SCBs是一组化学上不同的化合物，其结构不同于1，9-四氢大麻酚，因此难以检测其用途，并导致广泛滥用。医用大麻和109-THC已被证明是安全的。与此形成鲜明对比的是，没有关于K2中发现的任何SCB的安全性或有效性的信息，报告表明K2产品的许多临床效果与大麻产生的效果不同，可能存在健康风险。在这方面，我们通过LC-MS/MS对SCB使用者的尿样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SCBs的几种羟基化代谢产物在CB 1 R和CB 2 R上保持高亲和力和活性，并显着增加母体SCBs的急性效应。因此，在个体使用者中，SCB的生理效应可以代表1）由给定产品中SCB的不同混合物引起的“环境”效应，以及2）进一步受个体将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，重要的是要确定人体中SCB的代谢谱及其在CB 1 R和CB 2 R的生物活性。本项目的目标是阐明SCB及其代谢产物在人体CB 1 Rs和CB 2 Rs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。我们将测试的假设，在体内羟基化SCBs的细胞色素P450（CYP）和随后的共轭UDP-葡萄糖醛酸转移酶（UGT）和磺基转移酶（SULT）产生的高亲和力CB 1 R和CB 2 R激动剂，拮抗剂和反向激动剂的复杂混合物。这些代谢物与母体SCB“协同”作用，在人体内产生SCB的独特药理作用和毒性。我们的跨学科团队将通过四个具体目标来探索这一假设。目标1将采用LC-MS/MS法鉴定人尿液中K2产品中滥用的9种高优先级SCB的初级和次级代谢产物。还将收集每例患者的临床症状特征。目标2中的实验将表征负责SCB体外代谢的人I期和II期酶。在目标3中，将检查SCB及其代谢物结合并激活人CB 1 R和CB 2 R的能力。最后，目标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模拟作用。这个合作翻译项目将提供有关SCBs的代谢，药理学和毒理学的信息，以确定可能对公众的健康风险。