Indolealkylamine Metabolic Pharmacogenetics, Drug Interactions and Serotonin Toxicity
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Indolealkylamines (IAAs) are a class of chemical derivatives of monoamine neurotransmitter 5-hydroxytrypatmine (serotonin or 5-HT). Acting on serotonergic system, overdose or combined use of IAA drugs may induce severe or even fatal serotonin toxicity/syndrome. In this thesis, we employed 5-methyoxy- N,N -dimethyltryptamine (5-MeO-DMT), harmaline and pinoline as model IAA drugs to define IAA metabolism, drug interactions and serotonin toxicity. Wild-type and cytochrome P450 (CYP) 2D6 -humanized (Tg- CYP2D6 ) mice were used to delineate the impact of CYP2D6 pharmacogenetics, due to the fact that CYP2D6 catalyzes the O -demethylation of IAAs. First, pinoline O -demethylation was predominantly catalyzed by CYP2D6, and thus pinoline might serve as a probe for CYP2D6 activity at a proper concentration or dose. Second, concurrent harmaline significantly enhanced the systemic and brain exposure to 5-MeO-DMT and its active metabolite bufotenine, which was affected by CYP2D6 status. Third, pretreatment of harmaline potentiated 5-MeO-DMT-induced serotonin toxicity, as manifested by enhanced hyperthermia, hyperlocomotor activity and neuromuscular dysfunction, besides a sharp increase of acute toxicity. CYP2D6 status also partially influenced the drug effects at some dose combinations. Fourth, mechanistic studies revealed the critical roles of 5-HT 1A and 5-HT 2A receptors as well as their interplay in IAA-provoked serotonin toxicity, and a reduction of serotonin toxicity by 5-HT 1A and 5-HT 2A antagonists. Together, our studies provide new information about IAA metabolism, pharmacogenetics and complex drug interactions occurring at both pharmacokinetic and pharmacodynamics levels. It is also the first comprehensive characterization of IAA-induced clinically important serotonin toxicity/syndrome in mouse models and systemic study on the underlying serotonergic mechanism, which should provide helpful insight into the development of strategies for treating IAA-induced serotonin toxicity.