Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol.
Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol.
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DOI：
10.1021/acsmedchemlett.3c00017
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发表时间：
2023-05-11
影响因子：
4.2
通讯作者：
Jackson, Klarissa D.
中科院分区：
文献类型：
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作者：
Beers, Jessica L.;Authement, Aurora K.;Isoherranen, Nina;Jackson, Klarissa D.
大麻素大麻二酚（CBD）和δ-9-四氢大麻酚（THC）在肝脏中进行广泛的氧化代谢。虽然细胞色素P450形成CBD和THC的初级、生物活性、羟基化代谢物，但对分别产生CBD和THC的主要体内循环代谢物7-羧基-CBD和11-羧基-THC的酶知之甚少。本研究的目的是阐明参与形成这些代谢产物的酶。人肝亚细胞组分的辅因子依赖性实验表明，7-羧基-CBD和11-羧基-THC的形成在很大程度上依赖于细胞溶质NAD+依赖性酶，而NADPH依赖性微粒体酶的贡献较小。化学抑制剂的实验提供了证据，7-羧基-CBD的形成主要依赖于醛氧化酶，11-羧基-THC的形成也部分由醛氧化酶介导。这项研究是第一个证明细胞溶质药物代谢酶参与产生CBD和THC的主要体内代谢物，并解决了大麻素代谢的知识空白。
The cannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) undergo extensive oxidative metabolism in the liver. Although cytochromes P450 form the primary, pharmacologically active, hydroxylated metabolites of CBD and THC, less is known about the enzymes that generate the major in vivo circulating metabolites of CBD and THC, 7-carboxy-CBD and 11-carboxy-THC, respectively. The purpose of this study was to elucidate the enzymes involved in forming these metabolites. Cofactor dependence experiments with human liver subcellular fractions revealed that 7-carboxy-CBD and 11-carboxy-THC formation is largely dependent on cytosolic NAD+-dependent enzymes, with lesser contributions from NADPH-dependent microsomal enzymes. Experiments with chemical inhibitors provided evidence that 7-carboxy-CBD formation is mainly dependent on aldehyde dehydrogenases and 11-carboxy-THC formation is mediated also in part by aldehyde oxidase. This study is the first to demonstrate the involvement of cytosolic drug-metabolizing enzymes in generating major in vivo metabolites of CBD and THC and addresses a knowledge gap in cannabinoid metabolism.
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影响因子：
3.9
作者：
Beers, Jessica L.;Fu, Dong;Jackson, Klarissa D.
通讯作者：
Jackson, Klarissa D.
影响因子：
5.1
作者：
Lee, Shou-Lun;Shih, Hsuan-Ting;Yin, Shih-Jiun
通讯作者：
Yin, Shih-Jiun
影响因子：
7.3
作者：
Laprairie, R. B.;Bagher, A. M.;Denovan-Wright, E. M.
通讯作者：
Denovan-Wright, E. M.
影响因子：
6.1
作者：
Jiang, Rongrong;Yamaori, Satoshi;Watanabe, Kazuhito
通讯作者：
Watanabe, Kazuhito
DOI：
10.1124/dmd.121.000442
发表时间：
2021-12-01
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Nasrin, Shamema;Watson, Christy J W;Lazarus, Philip
通讯作者：
Lazarus, Philip