In vitrometabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4

Abstract

Women who experience hot flashes as a side effect of tamoxifen therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since pharmacological activity of tamoxifen is dependent on the metabolic conversion into active metabolites by the action of cytochromes P450 2D6 and 3A4, the objective of this study was to evaluate whether black cohosh extracts can inhibit formation of active tamoxifen metabolites and possibly reduce its clinical efficacy.At 50 µg/ml, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy-tamoxifen by 66.3%, N-desmethyl tamoxifen by 74.6% and α-hydroxy tamoxifen by 80.3%. In addition, using midazolam and dextromethorphan as probe substrates, this extract inhibited CYP3A4 and CYP2D6 with IC50 values of 16.5 and 50.1 µg/ml, respectively.Eight triterpene glycosides were identified as competitive CYP3A4 inhibitors with IC50 values ranging from 2.3–5.1 µM, while the alkaloids protopine and allocryptopine were identified as competitive CYP2D6 inhibitors with Ki values of 78 and 122 nM, respectively.The results of this study suggests that co-administration of black cohosh with tamoxifen might interfere with the clinical efficacy of this drug. However, additional clinical studies are needed to determine the clinical significance of these in vitro results.

Mass spectrometric dereplication of nitrogen-containing constituents of black cohosh (Cimicifuga racemosa L.)

“…For example, we found that protopine and allocryptopine are potent inhibitors of CYP2D6 and may be involved in potential interactions of black cohosh with drugs metabolized by this isoform such as tamoxifen [75]. …”

Herbal medicine for depression and anxiety:Asystematic review with assessment of potential psycho‐oncologic relevance

“…Although several studies reported herbal supplements to be safe, their potential for interactions with other drugs were not discussed. For example, black cohosh (Li et al, ), chasteberry (Ho, Singh, Holloway, & Crankshaw, ), chamomile (Ganzera, Schneider, & Stuppner, ), and rhodiola (Hellum et al, ) are known to modulate the actions of cytochrome P450 enzymes and may increase the toxicity or decrease therapeutic effects of substrate drugs (Gurley, Fifer, & Gardner, ) including many used in cancer treatment, such as cyclosporine (Sridharan & Sivaramakrishnan, ) and most of the tyrosine kinase inhibitors (Gay, Toulet, & Le Corre, ). Even though the clinical significance of these interactions is yet to be determined, the potential exists and therefore should be given due consideration.…”

Effects of herbal supplements on the bioactivation of chemotherapeutic agents

“…Initial evaluation of the data using Dixon plots suggested that the commercial preparations of SJW and BC used in this study inhibited the bioactivation of tamoxifen (mediated by CYP2D6, 3A4 and flavin‐containing monooxygenase) predominately by a non‐competitive mechanism, and that BC is a much stronger inhibitor of tamoxifen metabolism than SJW (Table ). Recently, it has been shown that at 50 μg/ml, a 75% ethanolic extract of BC inhibited the formation of 4‐hydroxytamoxifen by 66.3% and eight triterpenes identified did so via competitive inhibition of CYP3A4, with IC50 values of 5.1 µ m or less . From inhibition reactions of tamoxifen with GRE, the Dixon plot suggests that significant contributions to the overall inhibition were being made by multiple mechanisms, thus resulting in an indeterminate or mixed‐type mechanism.…”