Carbon-carbon Bond Cleavage Catalyzed by Human Cytochrome P450 Enzymes: α-ketol as the Key Intermediate Metabolite in Sequential Metabolism of Olanexidine

Author(s): Yiding Hu*, Yi Xiao, Zhesui Rao, Vasant Kumar, Hanlan Liu, Chuang Lu

Journal Name: Drug Metabolism Letters

Volume 14 , Issue 1 , 2021

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Graphical Abstract:


Background: Carbon-carbon bond cleavage of a saturated aliphatic moiety is rarely seen in xenobiotic metabolism. Olanexidine (Olanedine®), containing an n-octyl (C8) side chain, was mainly metabolized to various shortened side chain (C4 to C6) acid-containing metabolites in vivo in preclinical species. In liver microsomes and S9, the major metabolites of olanexidine were from multi-oxidation on its n-octyl (C8) side chain. However, the carbon-carbon bond cleavage mechanism of n-octyl (C8) side chain, and enzyme(s) responsible for its metabolism in human remained unknown.

Methods: A pair of regioisomers of α-ketol-containing C8 side chain olanexidine analogs (3,2-ketol olanexidine and 2,3-ketol olanexidine) were synthesized, followed by incubation in human liver microsomes, recombinant human cytochrome P450 enzymes or human hepatocytes, and subsequent metabolite identification using LC/UV/MS.

Results: Multiple shortened side chain (C4 to C6) metabolites were identified, including C4, C5 and C6- acid and C6-hydroxyl metabolites. Among 19 cytochrome P450 enzymes tested, CYP2D6, CYP3A4 and CYP3A5 were identified to catalyze carbon-carbon bond cleavage.

Conclusion: 3,2-ketol olanexidine and 2,3-ketol olanexidine were confirmed as the key intermediates in carbon-carbon bond cleavage. Its mechanism is proposed that a nucleophilic addition of iron-peroxo species, generated by CYP2D6 and CYP3A4/5, to the carbonyl group caused the carbon-carbon bond cleavage between the adjacent hydroxyl and ketone groups. As results, 2,3-ketol olanexidine formed a C6 side chain acid metabolite. While, 3,2-ketol olanexidine formed a C6 side chain aldehyde intermediate, which was either oxidized to a C6 side chain acid metabolite or reduced to a C6 side chain hydroxyl metabolite.

Keywords: Carbon-carbon bond cleavage, metabolism, cytochrome P450 enzyme, metabolic pathway, Olanexidine, ketol.

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Article Details

Year: 2021
Published on: 24 November, 2019
Page: [41 - 53]
Pages: 13
DOI: 10.2174/1872312813666191125095818
Price: $65

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