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 mu M), serotonin (K-i = 252 mu M and 167 mu M), dopamine (K-i = 49 mu M and 22 mu M), and histamine (K-i = 428 mu M and 359 mu M). Cotinine formation from nicotine was inhibited by tryptamine ( K-i = 0.7 mu M, competitive), serotonin (K-i = 272 mu M, noncompetitive), dopamine, noradrenaline, and adrenaline (K-i = 11 mu M, 54 mu M, and 81 mu M, uncompetitive). Estrogens ( K-i = 0.6 - 3.8 mu M), androgens ( K-i = 60-149 M), and corticosterone ( K-i = 36 mu M) 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 mu M), serotonin ( K-i = 316 mu M), dopamine ( K-i = 66 mu M), and histamine ( K-i = 209 mu M). 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.