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Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan (E.H., M.N., M.K., T.Y.); and Department of Legal Medicine, Dokkyo University School of Medicine, Tochigi, Japan (S.T.)

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 µM), serotonin (K_i = 252 µM and 167 µM), dopamine (K_i = 49 µM and 22 µM), and histamine (K_i = 428 µM and 359 µM). Cotinine formation from nicotine was inhibited by tryptamine (K_i = 0.7 µM, competitive), serotonin (K_i = 272 µM, noncompetitive), dopamine, noradrenaline, and adrenaline (K_i = 11 µM, 54 µM, and 81 µM, uncompetitive). Estrogens (K_i = 0.6–3.8 µM), androgens (K_i = 60–149 µM), and corticosterone (K_i = 36 µM) also inhibited cotinine formation, but coumarin 7-hydroxylation and cotinine 3'-hydroxylation did not. Nicotine-^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-^5'(1')-iminium ion formation was competitively inhibited by tryptamine (K_i = 0.3 µM), serotonin (K_i = 316 µM), dopamine (K_i = 66 µM), and histamine (K_i = 209 µM). 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.

This article has been cited by other articles:

				B Sinues, A Fanlo, E Mayayo, C Carcas, J Vicente, I Arenaz, and A Cebollada CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives Human and Experimental Toxicology, May 1, 2008; 27(5): 367 - 372. [Abstract] [PDF]

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