Metabolism of Nω‐methylserotonin,a serotonergic constituent of black cohosh (Cimicifuga racemosa,L. (Nutt.)), by human liver microsomes

The roots/rhizomes of black cohosh (Cimicifuga racemosa L. (Nutt.) (syn. Actaea racemosa L.) are a popular dietary supplements among women for management of menopausal symptoms. Although not estrogenic, N_ω‐methylserotonin has been identified in black cohosh as a potent agonist of serotonin 5‐HT_1A and 5‐HT₇ receptors. In the present study, in vitro metabolism of N_ω‐methylserotonin was investigated to gain insights into aspects of the bioavailability of this compound. The major metabolic pathway was determined to be conversion into 5‐hydroxyindole acetaldehyde catalyzed by the monoamine oxidase A (MAO‐A). 5‐Hydroxyindole acetaldehyde could be further oxidized to form 5‐hydroxyindole acetic acid by the action of microsomal aldehyde dehydrogenase or reduced to 5‐hydroxy tryptophol by the action of aldehyde reductase. The cytochrome P450 enzymes had only a minor role in the metabolism of N_ω‐methylserotonin and then only when MAO‐A was inhibited. In many aspects, the metabolism of N_ω‐methylserotonin was similar to the metabolism of serotonin, suggesting that this compound is unlikely to elicit CNS effects due to rapid metabolism by the widely distributed MAO‐A. Copyright © 2014 John Wiley & Sons, Ltd.