TY - JOUR T1 - HUMAN CYTOCHROME P450 INHIBITION AND METABOLIC-INTERMEDIATE COMPLEX FORMATION BY GOLDENSEAL EXTRACT AND ITS METHYLENEDIOXYPHENYL COMPONENTS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1391 LP - 1397 DO - 10.1124/dmd.31.11.1391 VL - 31 IS - 11 AU - Parnali Chatterjee AU - Michael R. Franklin Y1 - 2003/11/01 UR - http://dmd.aspetjournals.org/content/31/11/1391.abstract N2 - The concurrent use of herbal medicinals with prescription and over-the-counter drugs carries a risk for unanticipated adverse drug-botanical pharmacokinetic interactions, particularly as a result of cytochrome P450 (P450) inhibition. Extracts of goldenseal (Hydrastis canadensis) containing approximately equal concentrations (∼17 mM) of two methylenedioxyphenyl alkaloids, berberine and hydrastine, inhibited with increasing potency (CYP2C9) diclofenac 4′-hydroxylation, (CYP2D6) bufuralol 1′-hydroxylation, and (CYP3A4) testosterone 6β-hydroxylation activities in human hepatic microsomes. The inhibition of testosterone 6β-hydroxylation activity was noncompetitive with an apparent Ki of 0.11% extract. Of the methylenedioxyphenyl alkaloids, berberine (IC50 = 45 μM) was the more inhibitory toward bufuralol 1′-hydroxylation and hydrastine (IC50 ∼350 μM for both isomers), toward diclofenac 4′-hydroxylation. For testosterone 6β-hydroxylation, berberine was the least inhibitory component (IC50 ∼400 μM). Hydrastine inhibited testosterone 6β-hydroxylation with IC50 values for the (+)- and (-)-isomers of 25 and 30 μM, respectively. For (-)-hydrastine, an apparent Ki value of 18 μM without preincubation and an NADPH-dependent mechanism-based inhibition with a kinactivation of 0.23 min-1 and a KI of ∼110 μM were determined. Cytochrome P450 metabolic-intermediate (MI) complex formation could be demonstrated for both hydrastine isomers. With expressed P450 isoforms, hydrastine formed a P450 MI complex with CYP2C9, CYP2D6, and CYP3A4. Coexpression of cytochrome b5 with the P450 isoforms enhanced the rate but not the extent of P450 MI complex formation. The American Society for Pharmacology and Experimental Therapeutics ER -