title: Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?
abstract: Integration of genomic data from pharmacokinetic pathways and drug targets is an emerging trend in bioinformatics, but is there a clear separation of pharmacokinetic pathways and drug targets? Should we also consider the potential interactions of endogenous substrates of drug-metabolizing enzymes with receptors and other molecular drug targets as we combine pharmacogenomic datasets? We discuss these overarching questions through a specific pharmacogenomic case study of the cytochrome P450 (CYP)2D6, serotonin and dopamine triad. Importantly, CYP2D6 may contribute to the regeneration of serotonin from 5-methoxytryptamine by virtue of its catalytic function as a 5-methoxyindolethylamine O-demethylase. Furthermore, serotonergic neurons provide a regulatory feedback on dopaminergic neurotransmission. Hence, we hypothesize that independent of its role as a pharmacokinetic gene, CYP2D6 may nuance the regulation of serotonergic and dopaminergic neurophysiology. Additionally, we reflect upon the contribution of hyperspecialization in biomedicine to the present disconnect between research on pharmacokinetics and drug targets, and the potential for remedying this important gap through informed dialogue among clinical pharmacologists, human geneticists, bioethicists and applied social scientists.
authors.affiliation: Biomarker and Clinical Pharmacology Unit, University of California, Irvine, USA. m.vural.ozdemir@gmail.com
authors.forename: Vural
authors.initials: V
authors.lastname: Ozdemir
authors.forename: Arzu
authors.initials: A
authors.lastname: Gunes
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Dahl
authors.forename: M Gabriella
authors.initials: MG
authors.lastname: Scordo
authors.forename: Bryn
authors.initials: B
authors.lastname: Williams-Jones
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
mesh_terms: D008735:5-Methoxytryptamine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D010597:Pharmacogenetics; D012701:Serotonin / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D012701:Serotonin; D008735:5-Methoxytryptamine; D004295:Dihydroxyphenylalanine; D019389:Cytochrome P-450 CYP2D6