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 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-Δ^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-Δ^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.