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-methylserotonin has been identified in black cohosh as a potent agonist of serotonin 5-HT1A and 5-HT7 receptors. In the present study, in vitro metabolism of N-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-methylserotonin and then only when MAO-A was inhibited. In many aspects, the metabolism of N-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 (c) 2014 John Wiley & Sons, Ltd.