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SHORT COMMUNICATIONS: Eriko Higashi, Miki Nakajima, Miki Katoh, Shogo Tokudome, and Tsuyoshi Yokoi Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6 Drug Metab Dispos 2007; 35: 508-514 [Abstract] [Full text] [PDF]

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Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6

Jose AG Agundez, Guillermo Gervasini, Elena Garcia-Martin, Carmen Martinez   (6 April 2007)

Response to letter from J. Agundez

Miki Nakajima   (6 April 2007)

Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6 6 April 2007
Jose AG Agundez, Professor of Pharmacology Department of Pharmacology, Medical School, University of Extremadura., Guillermo Gervasini, Elena Garcia-Martin, Carmen Martinez Send letter to journal: Re: Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6 jagundez{at}unex.es Jose AG Agundez, et al.	Sir, Higashi et al. elegantly demonstrated that several neurotransmitters are able to inhibit CYP2A6 enzyme activity (Higashi et al., 2007). These findings are consistent with previous reports indicating inhibition of CYP1A2, CYP2D6, CYP2C9 and CYP3A4 by neurotransmitters (Martinez et al., 1997; Agundez et al., 1998; Martinez et al., 2000; Gervasini et al., 2001). Nevertheless, we would like to propose an alternative interpretation for some of the findings reported in such paper. Whereas Higashi et al. show a potent inhibitory effect for low concentrations of tryptamine and dopamine, inhibition caused by other compounds such as serotonin, histamine or adrenaline are observed only at high inhibitor concentrations. These high concentrations may affect the NADPH-cytochrome P450 reductase (E.C. 1.6.2.4) enzyme activity thus causing an artifactual inhibition of CYP2A6. Such effect may lead to misinterpretation of the findings regarding some low-potency inhibitors. NADPH-cytochrome P450 reductase inhibition is different for diverse neurotransmitters: for instance we have shown that 500 µM adrenaline cause a 35% inhibition of the NADPH-cytochrome P450 reductase, whereas no inhibition is caused by 500 µM tryptamine (Agundez et al., 1998). Since Higashi et al. reported some findings using inhibitor concentrations up to 1000 µM, to assess whether CYP2A6 is actually inhibited further work should focus on the inhibitory effect of high concentrations of these neurotransmitters on the coupled NADPH-cytochrome P450 reductase and cytochrome b5 enzyme activities. Such study would significantly add to the interesting findings reported by Higashi et al (Higashi et al., 2007) and to further studies assessing the effect of neurotransmitters on cytochrome P450 enzyme activities. References Agundez JA, Gallardo L, Martinez C, Gervasini G and Benitez J (1998) Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine. Pharmacogenetics 8:251-258. Gervasini G, Martinez C, Agundez JA, Garcia-Gamito FJ and Benitez J (2001) Inhibition of cytochrome P450 2C9 activity in vitro by 5- hydroxytryptamine and adrenaline. Pharmacogenetics 11:29-37. Higashi E, Nakajima M, Katoh M, Tokudome S and Yokoi T (2007) Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6. Drug Metab Dispos 35:508-514. Martinez C, Agundez JA, Gervasini G, Martin R and Benitez J (1997) Tryptamine: a possible endogenous substrate for CYP2D6. Pharmacogenetics 7:85-93. Martinez C, Gervasini G, Agundez JA, Carrillo JA, Ramos SI, Garcia- Gamito FJ, Gallardo L and Benitez J (2000) Modulation of midazolam 1- hydroxylation activity in vitro by neurotransmitters and precursors. Eur J Clin Pharmacol 56:145-151.
Response to letter from J. Agundez 6 April 2007
Miki Nakajima Kanazawa University Send letter to journal: Re: Response to letter from J. Agundez nmiki{at}kenroku.kanazawa-u.ac.jp Miki Nakajima	We found that the inhibitory effects of tryptamine on CYP2A6 activities (Ki = 0.2 – 0.3 µM) (Higashi et al., 2007) were more potent than those on CYP1A2 (Ki = 40 µM) (Agúndez et al., 1998), CYP2C9 (Ki = 340 µM) (Gervasini et al., 2001), CYP2D6 (IC50 = 45 µM) (Martínez et al., 1997), and CYP3A4 (Ki > 500 µM) (Martínez et al., 2000) activities. In contrast, the inhibitory effects of serotonin on CYP2A6 activities (Ki = 167 – 316 µM) were less potent than those on CYP1A2 (Ki = 35 µM) (Agúndez et al., 1998), CYP2C9 (Ki = 63.5 µM) (Gervasini et al., 2001), CYP2D6 (IC50 = 25 µM) (Martínez et al., 1997), and CYP3A4 (Ki = 26 µM) (Martínez et al., 2000) activities. Agúndez et al (1998) have reported that the residual activity of NADPH-cytochrome P450 reductase (CPR) in the presence of 500 µM tryptamine and serotonin were 97% and 93%, respectively. Thus, their inhibitory effects would be a direct one toward each CYP isoform. We also found that the inhibitory effects of dopamine on CYP2A6 activities (Ki = 22 – 66 µM) were more potent than those on CYP1A2 (Ki = 520 µM) (Agúndez et al., 1998), CYP2C9 (Ki = 405 µM) (Gervasini et al., 2001), CYP2D6 (IC50 = 155 µM) (Martínez et al., 1997), and CYP3A4 (Ki = 420 µM) (Martínez et al., 2000) activities. Although we could not find any report regarding the inhibitory effects of dopamine on CPR activity, dopamine would selectively inhibit CYP2A6. Agúndez et al (1998) reported that adrenaline weakly inhibited CPR activity (the residual activity was 65% in the presence of 500 µM adrenaline). The inhibitory effects of adrenaline on coumarin 7-hydroxylation, cotinine 3’-hydroxylation, and nicotine- Δ5’(1’)-iminium ion formation from nicotine were trivial, but were prominent for cotinine formation from nicotine. Therefore we concluded that adrenaline has prominent inhibitory potency for aldehyde oxidase. We found that histamine moderately inhibited CYP2A6 activity (Ki = 209 – 428 µM). It is worth pursuing whether the inhibition might be a result of inhibition of CPR activity. We also consider that it is interesting to investigate the effects of endogenous compounds on the CPR as well as cytochrome b5 activities. Such studies will be performed in the near future. References Agúndez JA, Gallardo L, Martínez C, Gervasini G, and Benítez J (1998) Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine. Pharmacogenetics 8: 251-258. Gervasini G, Martínez C, Agúndez JA, García-Gamito FJ, and Benítez J (2001) Inhibition of cytochrome P450 2C9 activity in vitro by 5- hydroxytryptamine and adrenaline. Pharmacogenetics 11: 29-37. Higashi E, Nakajima M, Katoh M, Tokudome S, and Yokoi T (2007) Inhibitory effects of neurotransmitters and steroids on human CYP2A6. Drug Metab Dispos 35: 508-514. Martínez C, Agúndez JA, Gervasini G, Martín R, and Benítez J (1997) Tryptamine: a possible endogenous substrate for CYP2D6. Pharmacogenetics 7: 85-93. Martínez C, Gervasini G, Agúndez JA, Carrillo JA, Ramos SI, García- Gamito FJ, Gallardo L, and Benítez J (2000) Modulation of midazolam 1- hydroxylation activity in vitro by neurotransmitters and precursors. Eur J Clin Pharmacol 56: 145-151.