ArticleDrug metabolism and disposition: the biological fate of chemicals2006
CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime].
Article in Drug metabolism and disposition: the biological fate of chemicals, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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39 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
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- Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro.Molecules (Basel, Switzerland) · 2018Article
- Unravelling the Molecular Determinants of Bee Sensitivity to Neonicotinoid Insecticides.Current biology : CB · 2018Article
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- Effect of Genetic Variability in theFrontiers in pharmacology · 2017Article
- Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs.Journal of biomolecular screening · 2016Article
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- Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer.Advances in pharmacology (San Diego, Calif.) · 2015Review
- PharmGKB summary: very important pharmacogene information for CYP4F2.Pharmacogenetics and genomics · 2015Review
- In vitro and in vivo evaluation of 28DAP010, a novel diamidine for treatment of second-stage African sleeping sickness.Antimicrobial agents and chemotherapy · 2014Article
- The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
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16 authors at 5 institutions in 2 countries.
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Abstract
DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH-cytochrome b5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLMs) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by P450 enzymes. M1 formation by HLMs was NADPH-dependent, with a Km and Vmax of 0.5 microM and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLMs. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLMs. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.
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