Studies on the metabolism of the Δ9-tetrahydrocannabinol precursor Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques
Studies on the metabolism of the Δ9-tetrahydrocannabinol precursor Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques
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DOI：
10.1002/jms.1624
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发表时间：
2009-10-01
影响因子：
2.3
通讯作者：
Auwaerter, Volker
中科院分区：
文献类型：
--
作者：
Jung, Julia;Meyer, Markus R.;Auwaerter, Volker
在大麻中，Delta 9-四氢大麻酚酸-A(Delta 9-THCA-A)是Delta 9-四氢大麻酚(Delta 9-THC)的非精神活性前体。在新鲜的植物材料中，大约90%的Delta 9-THC以Delta 9-THCA-A的形式存在。加热(烟熏或烘焙)时，Delta 9-THCA只部分转化为Delta 9-THC，因此可以在大麻消费者的血清和尿液中检测到Delta 9-THCA-A。本研究的目的是鉴定Delta 9-THCA-A的代谢物，特别是研究口服Delta 9-THCA-A是否会在大鼠模型中导致Delta 9-THC的体内形成。大鼠灌胃给予Delta9-THCA-A(15 mg/kg体重)后，采集尿样，用液相色谱-质谱仪(LC-MS)、液质联用仪(LC-MS/MS)和高分辨LC-MS-飞行时间质谱仪(TOF-MS)进行准确的质量测定。为了检测Delta 9-THC及其代谢物，用气相色谱-质谱仪(GC-MS)分析了尿液提取物。已鉴定的代谢物表明Delta 9-THCA-A在11-羟基-Delta 9-四氢大麻酸-A(11-OH-Delta 9-THCa-A)位置发生羟基化，再通过中间体11-氧代-Delta 9-THCA进一步氧化为11-Nor-9-羧基-Delta 9-四氢大麻酚酸-A(Delta 9-THCa-A-COOH)。在大鼠的尿液中也发现了母体化合物和两种主要代谢物的葡萄糖醛酸苷。此外，Delta 9-THCA分别在8到8-α和8-β-羟基-Delta 9-四氢大麻酚酸-A位进行羟基化(分别为8α-羟基-Delta 9-THCA和8β-羟基-Delta 9-THCA-A)，然后脱水。两种单羟基代谢物都被进一步氧化成其双羟化形式。鉴定了这些代谢物的几种葡萄糖醛酸化偶联物。在体内没有观察到Delta 9-THCA向Delta 9-THC的转化。版权所有(C)2009 John Wiley&Sons，Ltd.
In Cannabis sativa, Delta 9-Tetrahydrocannabinolic acid-A (Delta 9-THCA-A) is the non-psychoactive precursor of Delta 9-tetrahydrocannabinol (Delta 9-THC). In fresh plant material, about 90% of the total Delta 9-THC is available as Delta 9-THCA-A. When heated (smoked or baked), Delta 9-THCA-A is only partially converted to Delta 9-THC and therefore, Delta 9-THCA-A can be detected in serum and urine of cannabis consumers. The aim of the presented study was to identify the metabolites of Delta 9-THCA-A and to examine particularly whether oral intake of Delta 9-THCA-A leads to in vivo formation of Delta 9-THC in a rat model. After oral application of pure Delta 9-THCA-A to rats (15 mg/kg body mass), urine samples were collected and metabolites were isolated and identified by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high resolution LC-MS using time of flight-mass spectrometry (TOF-MS) for accurate mass measurement. For detection of Delta 9-THC and its metabolites, urine extracts were analyzed by gas chromatography-mass spectrometry (GC-MS). The identified metabolites show that Delta 9-THCA-A undergoes a hydroxylation in position 11 to 11-hydroxy-Delta 9-tetrahydrocannabinolic acid-A (11-OH-Delta 9-THCA-A), which is further oxidized via the intermediate aldehyde 11-oxo-Delta 9-THCA-A to 11-nor-9-carboxy-Delta 9-tetrahydrocannabinolic acid-A (Delta 9-THCA-A-COOH). Glucuronides of the parent compound and both main metabolites were identified in the rat urine as well. Furthermore, Delta 9-THCA-A undergoes hydroxylation in position 8 to 8-alpha- and 8-beta-hydroxy-Delta 9-tetrahydrocannabinolic acid-A, respectively, (8 alpha-Hydroxy-Delta 9-THCA-A and 8 beta-Hydroxy-Delta 9-THCA-A, respectively) followed by dehydration. Both monohydroxylated metabolites were further oxidized to their bishydroxylated forms. Several glucuronidation conjugates of these metabolites were identified. In vivo conversion of Delta 9-THCA-A to Delta 9-THC was not observed. Copyright (C) 2009 John Wiley & Sons, Ltd.