Human cytochrome P450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components

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 (similar to17 mM) of two methylenedioxyphenyl alkaloids, berberine and hydrastine, inhibited with increasing potency (CYP2C9) diclofenac 4'-hydroxylation, (CYP2D6) bufuralol 1'-hydroxylation, and (CYP3A4) testosterone 6beta-hydroxylation activities in human hepatic microsomes. The inhibition of testosterone 6beta-hydroxylation activity was noncompetitive with an apparent K-i of 0.11% extract. Of the methylenedioxyphenyl alkaloids, berberine (IC50 = 45 muM) was the more inhibitory toward bufuralol 1'-hydroxylation and hydrastine (IC50 similar to 350 muM for both isomers), toward diclofenac 4'-hydroxylation. For testosterone 6beta-hydroxylation, berberine was the least inhibitory component (IC50 similar to 400 muM). Hydrastine inhibited testosterone 6beta-hydroxylation with IC50 values for the (+)- and (-)-isomers of 25 and 30 muM, respectively. For (-)- hydrastine, an apparent K-i value of 18 muM without preincubation and an NADPH-dependent mechanism-based inhibition with a k(inactivation) of 0.23 min(-1) and a K-I of similar to110 muM 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 b(5) with the P450 isoforms enhanced the rate but not the extent of P450 MI complex formation.