依赖NADP的酒精氧化还原酶氧化7-氧化二醇到一个活性甲基甲基甲酸盐
Qiangen Wu1, Jia-Long Fang2, Suresh K Nagumalli2
1Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA. Qiangen.Wu@fda.hhs.gov.
Archives of toxicology
|July 30, 2025
概括
大麻二醇 (CBD) 通过7型甲基-CBD中间体代谢为7-基-CBD,然后通过7型甲基-CBD代谢为7-基-CBD. 依赖NAD(P) +的酒精氧化还原酶和化脱酶催化这种途径,这可能对CBD细胞毒性产生潜在影响.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
- 药物新陈代谢 药物新陈代谢
背景情况:
- 大麻素 (CBD) 通过细胞P450酶被氧化成7--CBD.
- 7-基-CBD进一步代谢为7-基-CBD,这是人类的主要代谢物.
- 中间体7-甲基-CBD的形成和酶途径在很大程度上仍然没有表征.
研究的目的:
- 为了研究从7-基-CBD中形成7-formyl-CBD的形成和酶途径.
- 为了确定参与将7-甲基-CBD转化为7-碳氧-CBD的酶.
- 探索7-基-CBD积累在7-基-CBD细胞毒性中的作用.
主要方法:
- 用人肝 S9 分数和显微体化 7-基-CBD.
- 使用O-(2,3,4,5,6-pentafluorobenzyl) 胺 (PFBHA) 作为7-甲基-CBD的捕获剂.
- 使用黄类药物 (kaempferol),酒精氧化降解酶/基类固醇脱酶抑制剂和化脱酶抑制剂 (disulfiram,WIN 18,446) 的酶抑制研究.
主要成果:
- 从7-基-CBD中证明了7-formyl-CBD (作为7-pentafluorobenzyl oxime-CBD) 的形成,需要NAD+或NADP+.
- 捕获7-甲基-CBD减少了7-碳氧-CBD的形成,证实了7-甲基-CBD作为前体.
- 凯姆菲洛和某些基类固醇抑制了7-甲基-CBD和7-碳氧-CBD的形成,这表明酒精氧化还原酶的参与.
- 阿尔德脱酶抑制剂增加了7-甲基-CBD的积累,并可能增强了7-基-CBD的细胞毒性.
结论:
- 在人体肝脏中,NAD(P) +依赖的酒精氧化降解酶可能催化7-基-CBD转化为7-甲基-CBD.
- 化脱酶进一步将7-甲基-CBD氧化为7-碳氧-CBD.
- 阿尔德中间体的积累可能会导致细胞毒性,特别是与阿尔德脱酶抑制剂同时使用时.
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