title: Inhibitory effects of neurotransmitters and steroids on human CYP2A6.
abstract: Human CYP2A6 catalyzes the metabolism of nicotine, cotinine, and coumarin as well as some pharmaceutical drugs. CYP2A6 is highly expressed in liver and, also, in brain and steroid-related tissues. In this study, we investigated the inhibitory effects of neurotransmitters and steroid hormones on CYP2A6 activity. We found that coumarin 7-hydroxylation and cotinine 3'-hydroxylation by recombinant CYP2A6 expressed in baculovirus-infected insect cells were competitively inhibited by tryptamine (both K(i) = 0.2 microM), serotonin (K(i) = 252 microM and 167 microM), dopamine (K(i) = 49 microM and 22 microM), and histamine (K(i) = 428 microM and 359 microM). Cotinine formation from nicotine was inhibited by tryptamine (K(i) = 0.7 microM, competitive), serotonin (K(i) = 272 microM, noncompetitive), dopamine, noradrenaline, and adrenaline (K(i) = 11 microM, 54 microM, and 81 microM, uncompetitive). Estrogens (K(i) = 0.6-3.8 microM), androgens (K(i) = 60-149 microM), and corticosterone (K(i) = 36 microM) also inhibited cotinine formation, but coumarin 7-hydroxylation and cotinine 3'-hydroxylation did not. Nicotine-Delta(5'(1'))-iminium ion formation from nicotine was not affected by these steroid hormones, indicating that the inhibition of cotinine formation was due to the inhibitory effects on aldehyde oxidase. The nicotine-Delta(5'(1'))-iminium ion formation was competitively inhibited by tryptamine (K(i) = 0.3 microM), serotonin (K(i) = 316 microM), dopamine (K(i) = 66 microM), and histamine (K(i) = 209 microM). Thus, we found that some neurotransmitters inhibit CYP2A6 activity, being related with inter- and intraindividual differences in CYP2A6-dependent metabolism. The inhibitory effects of steroid hormones on aldehyde oxidase may also contribute to interindividual differences in nicotine metabolism.
authors.affiliation: Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. nmiki@kenroku.kanazawa-u.ac.jp
authors.forename: Eriko
authors.initials: E
authors.lastname: Higashi
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Miki
authors.initials: M
authors.lastname: Katoh
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokudome
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000728:Androgens; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive; D002460:Cell Line; D003345:Corticosterone; D003374:Coumarins / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004837:Epinephrine / Q000378:metabolism; D004967:Estrogens; D006632:Histamine / Q000378:metabolism; D006728:Hormones / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007313:Insecta; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D009538:Nicotine / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014363:Tryptamines / Q000378:metabolism
chemical_list: D000728:Androgens; D003374:Coumarins; D004791:Enzyme Inhibitors; D004967:Estrogens; D006728:Hormones; D018377:Neurotransmitter Agents; D011994:Recombinant Proteins; D014363:Tryptamines; D012701:Serotonin; C030820:tryptamine; D009538:Nicotine; D006632:Histamine; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D042931:Aldehyde Oxidase; D004298:Dopamine; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine