McDonald, Matthew G. published the artcileModulation of major human liver microsomal cytochromes P450 by component alkaloids of goldenseal: time-dependent inhibition and allosteric effects, Synthetic Route of 40180-04-9, the main research area is human liver microsomal cytochrome alkaloid goldenseal allosteric effect.
Botanical and other natural products (NPs) are often coconsumed with prescription medications, presenting a risk for cytochrome P 450 (P 450)-mediated NP-drug interactions. The NP goldenseal (Hydrastis canadensis) has exhibited antimicrobial activities in vitro attributed to isoquinoline alkaloids contained in the plant, primarily berberine, (-)-β hydrastine, and to a lesser extent, hydrastinine. These alkaloids contain methylenedioxyphenyl rings, structural alerts with potential to inactivate P450s through formation of metabolic intermediate complexes. Time-dependent inhibition experiments were conducted to evaluate their ability to inhibit major P 450 activities in human liver microsomes by using a cocktail of isoenzyme-specific substrate probes. Berberine inhibited CYP2D6 (dextromethorphan O-demethylation; KI = 2.7μM, kinact = 0.065 min-1) and CYP3A4/5 (midazolam 1′-hydroxylation; KI = 14.8μM, kinact = 0.019 min-1); (-)-β-hydrastine inhibited CYP2C9 (diclofenac 4′-hydroxylation; KI = 49 ηM, kinact = 0.036 min-1), CYP2D6 (KI > 250μM, kinact > 0.06 min-1), and CYP3A4/5 (KI = 28μM, kinact = 0.056 min-1); and hydrastinine inhibited CYP2D6 (KI = 37μM, kinact = 0.049 min-1) activity. Berberine addnl. exhibited allosteric effects on midazolam hydroxylation, showing both pos. and neg. heterotropic cooperativity. Experiments with recombinant isoenzymes showed that berberine activated midazolam 1′-hydroxylation by CYP3A5, lowering Km(app), but showed mixed inhibition and neg. cooperativity toward this reaction when catalyzed by CYP3A4. Berberine inactivated CYP3A4 at a much faster rate than CYP3A5 and was a noncompetitive inhibitor of midazolam 4-hydroxylation by CYP3A4 but a strong mixed inhibitor of the CYP3A5 catalyzed reaction. These complex kinetics should be considered when extrapolating the risk for NP-drug interactions involving goldenseal. Robust kinetic parameters were determined for the reversible and timedependent inhibition of CYP2C9, CYP2D6, and CYP3A4/5 activities in human liver microsomes by major component isoquinoline alkaloids contained in the botanical natural product goldenseal. The alkaloid berberine also exhibited opposing, isoenzyme-specific allosteric effects on midazolam hydroxylation mediated by recombinant CYP3A4 (inhibition) and CYP3A5 (activation). These data will inform the development of a physiol. based pharmacokinetic model that can be used to predict potential clin. relevant goldenseal-drug interactions.
Drug Metabolism & Disposition published new progress about Alkaloids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Synthetic Route of 40180-04-9.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem