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<p>Cannabidiol (CBD) undergoes oxidation to 7-hydroxy-CBD in the liver via cytochrome P450 enzymes. 7-Hydroxy-CBD can be further oxidized to 7-carboxy-CBD, the principal circulating metabolite in humans. An aldehyde intermediate, 7-formyl-CBD, is hypothesized to be the precursor of 7-carboxy-CBD; however, the formation of 7-formyl-CBD and the enzymes leading to its formation and metabolism have not been thoroughly investigated. Upon incubating 7-hydroxy-CBD with human liver S9 or microsomes, and using <i>O</i>-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) as a trapping agent, we demonstrated the formation of 7-formyl-CBD as its oxime derivative 7-pentafluorobenzyl oxime-CBD (7-PFBO-CBD). The transformation of 7-hydroxy-CBD to 7-formyl-CBD in S9 or microsomes required NAD<sup>+</sup> or NADP<sup>+</sup>. Trapping 7-formyl-CBD with PFBHA decreased the formation of 7-carboxy-CBD, indicating that the formation of 7-carboxy-CBD depends on the availability of 7-formyl-CBD. The flavonoid kaempferol, which inhibits xanthine oxidoreductase and hydroxysteroid dehydrogenases, suppressed the formation of 7-PFBO-CBD and 7-carboxy-CBD in human liver S9 and microsomes incubated with 7-hydroxy-CBD. The xanthine oxidoreductase inhibitor allopurinol and its substrate xanthine did not affect the metabolism of 7-hydroxy-CBD. The hydroxysteroids estradiol and dehydroepiandrosterone reduced the formation of 7-carboxy-CBD in liver microsomes and S9. These results suggest that alcohol oxidoreductases associated with hydroxysteroid metabolism may play a role in the conversion of 7-hydroxy-CBD to 7-formyl-CBD. The irreversible aldehyde dehydrogenase inhibitors, disulfiram and WIN 18,446, inhibited the formation of 7-carboxy-CBD and led to a significant accumulation of 7-PFBO-CBD in the S9 and microsomal incubations. The accumulation of the aldehyde intermediate may play a role in the enhanced cytotoxicity of 7-hydroxy-CBD in HepG2 cells when co-treated with disulfiram. These findings indicate that NAD(P)<sup>+</sup>-dependent alcohol oxidoreductases may catalyze the conversion of 7-hydroxy-CBD to 7-formyl-CBD in human liver S9 and microsomes. The potentially toxic aldehyde intermediate is further oxidized by aldehyde dehydrogenase to 7-carboxy-CBD.</p>

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NAD(P)+-dependent alcohol oxidoreductases oxidize 7-hydroxycannabidiol to a reactive formyl metabolite

  • 期刊论文

  • 发表日期：

    2025年7月30日

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  • Qiangen Wu,
  • Jia-Long Fang,
  • Suresh K. Nagumalli,
  • Xiaoqing Guo,
  • Frederick A. Beland

摘要

Cannabidiol (CBD) undergoes oxidation to 7-hydroxy-CBD in the liver via cytochrome P450 enzymes. 7-Hydroxy-CBD can be further oxidized to 7-carboxy-CBD, the principal circulating metabolite in humans. An aldehyde intermediate, 7-formyl-CBD, is hypothesized to be the precursor of 7-carboxy-CBD; however, the formation of 7-formyl-CBD and the enzymes leading to its formation and metabolism have not been thoroughly investigated. Upon incubating 7-hydroxy-CBD with human liver S9 or microsomes, and using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) as a trapping agent, we demonstrated the formation of 7-formyl-CBD as its oxime derivative 7-pentafluorobenzyl oxime-CBD (7-PFBO-CBD). The transformation of 7-hydroxy-CBD to 7-formyl-CBD in S9 or microsomes required NAD+ or NADP+. Trapping 7-formyl-CBD with PFBHA decreased the formation of 7-carboxy-CBD, indicating that the formation of 7-carboxy-CBD depends on the availability of 7-formyl-CBD. The flavonoid kaempferol, which inhibits xanthine oxidoreductase and hydroxysteroid dehydrogenases, suppressed the formation of 7-PFBO-CBD and 7-carboxy-CBD in human liver S9 and microsomes incubated with 7-hydroxy-CBD. The xanthine oxidoreductase inhibitor allopurinol and its substrate xanthine did not affect the metabolism of 7-hydroxy-CBD. The hydroxysteroids estradiol and dehydroepiandrosterone reduced the formation of 7-carboxy-CBD in liver microsomes and S9. These results suggest that alcohol oxidoreductases associated with hydroxysteroid metabolism may play a role in the conversion of 7-hydroxy-CBD to 7-formyl-CBD. The irreversible aldehyde dehydrogenase inhibitors, disulfiram and WIN 18,446, inhibited the formation of 7-carboxy-CBD and led to a significant accumulation of 7-PFBO-CBD in the S9 and microsomal incubations. The accumulation of the aldehyde intermediate may play a role in the enhanced cytotoxicity of 7-hydroxy-CBD in HepG2 cells when co-treated with disulfiram. These findings indicate that NAD(P)+-dependent alcohol oxidoreductases may catalyze the conversion of 7-hydroxy-CBD to 7-formyl-CBD in human liver S9 and microsomes. The potentially toxic aldehyde intermediate is further oxidized by aldehyde dehydrogenase to 7-carboxy-CBD.