Garlic Metabolism and Cytochrome P450 Modulation

大蒜代谢和细胞色素 P450 调节

• 批准号: 6902421
• 负责人: DANNY D SHEN
• 金额: $ 21.63万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902421
• 关键词: P glycoprotein; alternative medicine; angiosperms; blood tests; breath tests; clinical research; cytochrome P450; dietary supplements; drug interactions; drug metabolism; enzyme induction /repression; food processing /preparation; human subject; nutrient interaction; nutrition related tag; pharmacokinetics; physical chemical interaction; physical state; plant extracts; urinalysis; vegetable oils

DESCRIPTION (provided by applicant): Garlic supplements are widely used for the treatment of high blood cholesterol and lipids. Until recently, garlic supplements were thought to be well tolerated and relatively safe. Adverse interactions between garlic supplements and several narrow therapeutic drugs, including anticoagulants (warfarin, fuindione) and HIV protease inhibitors (saquinavir, ritonavir), have been reported within the past 2 years. Animal and in vitro studies with known organosulfur constituents of garlic, as well as garlic extracts, are known to simultaneously inhibit and induce several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa. However, very recent studies in human subjects have produced conflicting data as to the effects of garlic supplements on cytochrome P450 function. Our specific hypotheses are: 1) the effects of garlic supplements on CYP and Pgp function vary with the type of garlic preparation (viz. garlic powder, steamed-distilled garlic oil, and aged garlic); and 2) garlic's effect is time- and regimen-dependent (e.g. it acutely inhibits and chronically induces CYP3A4 and Pgp activities in human subjects). Two separate "cocktails" of CYP and Pgp probe substrates, including caffeine (1A2), buproprion (2B6), chlorzoxazone (2E1), tolbutamide (2C9), omeprazole (2C19), metoprolol (2D6), midazolam (3A4/5), and digoxin (Pgp), will be administered to a panel of healthy human volunteers at various times during and shortly after discontinuation of daily intake of garlic supplement. Pharmacokinetics of known bioactive garlic constituents and their biotransformation products will be simultaneously studied through collection of blood, breath and urine samples. Garlic metabolite data may offer clues as to which garlic-derived compounds may be responsible for the putative metabolic effects. Specifically, we will measure metabolites deriving from allicin and allylic sulfides, which are the main constituents of garlic powder and garlic oil. We will also measure metabolites of S-allylcysteine, which is derived from hydrolysis of allylic cysteinyl peptides in garlic powder and aged garlic. These metabolic studies in human subjects will be conducted at the University of Washington General Clinical Research Center. The results will provide critical information for the design of further clinical studies to characterize and elucidate potentially important adverse garlic-drug interactions.

描述（申请人提供）：大蒜补充剂广泛用于治疗高胆固醇和高血脂。直到最近，大蒜补充剂还被认为具有良好的耐受性并且相对安全。过去两年已有报道称大蒜补充剂与几种狭义治疗药物之间存在不良相互作用，包括抗凝剂（华法林、呋喃二酮）和 HIV 蛋白酶抑制剂（沙奎那韦、利托那韦）。对大蒜已知有机硫成分以及大蒜提取物进行的动物和体外研究表明，大蒜提取物可以同时抑制和诱导肝脏中的多种 CYP 酶（1A、2B、2C、2E 和 3A 亚家族）以及外排转运蛋白肠粘膜中的 P-糖蛋白 (Pgp)。然而，最近针对人类受试者的研究得出了关于大蒜补充剂对细胞色素 P450 功能的影响的相互矛盾的数据。我们的具体假设是：1）大蒜补充剂对 CYP 和 Pgp 功能的影响因大蒜制剂的类型（即大蒜粉、蒸蒸馏蒜油和陈蒜）而异； 2) 大蒜的作用具有时间和治疗方案依赖性（例如，它在人类受试者中急性抑制并长期诱导 CYP3A4 和 Pgp 活性）。 CYP 和 Pgp 探针底物的两种独立“鸡尾酒”，包括咖啡因 (1A2)、安非他酮 (2B6)、氯唑沙宗 (2E1)、甲苯磺丁脲 (2C9)、奥美拉唑 (2C19)、美托洛尔 (2D6)、咪达唑仑 (3A4/5)、和地高辛（Pgp），将在一组健康人类志愿者中进行注射在停止每日摄入大蒜补充剂期间和之后不久的不同时间。将通过收集血液、呼吸和尿液样本同时研究已知生物活性大蒜成分及其生物转化产物的药代动力学。大蒜代谢物数据可能提供线索，说明哪些大蒜衍生的化合物可能造成假定的代谢效应。具体来说，我们将测量大蒜素和烯丙基硫化物的代谢物，它们是大蒜粉和大蒜油的主要成分。我们还将测量 S-烯丙基半胱氨酸的代谢物，它源自大蒜粉和陈蒜中烯丙基半胱氨酸肽的水解。这些人体代谢研究将在华盛顿大学综合临床研究中心进行。结果将为进一步临床研究的设计提供关键信息，以表征和阐明潜在的重要的大蒜-药物不良相互作用。