RT Journal Article
SR Electronic
T1 Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 508
OP 514
DO 10.1124/dmd.106.014084
VO 35
IS 4
A1 Higashi, Eriko
A1 Nakajima, Miki
A1 Katoh, Miki
A1 Tokudome, Shogo
A1 Yokoi, Tsuyoshi
YR 2007
UL http://dmd.aspetjournals.org/content/35/4/508.abstract
AB 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 Ki = 0.2 μM), serotonin (Ki = 252 μM and 167 μM), dopamine (Ki = 49 μM and 22 μM), and histamine (Ki = 428 μM and 359 μM). Cotinine formation from nicotine was inhibited by tryptamine (Ki = 0.7 μM, competitive), serotonin (Ki = 272 μM, noncompetitive), dopamine, noradrenaline, and adrenaline (Ki = 11 μM, 54 μM, and 81 μM, uncompetitive). Estrogens (Ki = 0.6–3.8 μM), androgens (Ki = 60–149 μM), and corticosterone (Ki = 36 μM) also inhibited cotinine formation, but coumarin 7-hydroxylation and cotinine 3′-hydroxylation did not. Nicotine-Δ5′(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-Δ5′(1′)-iminium ion formation was competitively inhibited by tryptamine (Ki = 0.3 μM), serotonin (Ki = 316 μM), dopamine (Ki = 66 μM), and histamine (Ki = 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. The American Society for Pharmacology and Experimental Therapeutics