Inhibitory effects of neurotransmitters and steroids on human CYP2A6.
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.
Higashi
Eriko
E
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
Nakajima
Miki
M
Katoh
Miki
M
Tokudome
Shogo
S
Yokoi
Tsuyoshi
T
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
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