MODULATION OF CYP1A2 ENZYME-ACTIVITY BY INDOLEAMINES - INHIBITION BY SEROTONIN AND TRYPTAMINE

Recent evidence supports a role for the CYP2D6 enzyme in the metabolis m of tryptamine, Because of the partial overlapping between substrate and inhibitor specificities that characterize some cytochrome P450 enz ymes, these findings raise the possibility that other cytochrome P450 enzymes may be modulated by endogenous compounds. In the present study , the occurrence of modulatory effect of 17 neurotransmitters, precurs ors and metabolites on the cytochrome P450 1A2 (CYP1A2) enzyme activit y was studied in human liver microsomes. Two indoleamines, serotonin a nd tryptamine, showed a competitive inhibitory effect on the high-affi nity component of the phenacetin O-de-ethylase activity, Both substanc es induced an inhibition of 100% of the activity with K-i values of 35 and 45 mu M for serotonin and tryptamine, respectively, The inhibitor s did not affect the microsomal NADPH-reductase activity. Other substa nces, which were either poor or partial inhibitors, were dopamine, L-t yrosine, tryptophol, 5-hydroxytryptophol, adrenaline, indole-3-acetald ehyde, 5-hydroxytryptophan, noradrenaline, vanillylmandelic acid, indo le-3-acetic acid, dihydroxyphenylacetic acid, and homovanillic acid. L -tryptophan, dihydroxy-phenylalanine and 5-hydroxyindole acetic acid i nduced very low or no inhibitory effect. Tryptamine and serotonin meta bolism in human liver microsomes was studied after inhibition of monoa mine oxidase activity with the unspecific MBO inhibitor pargyline. Bot h serotonin and tryptamine were metabolized in human liver microsomes. However; the metabolism of both indoleamines was not significantly in hibited with the CYP1A2-specific inhibitor furafylline, thus indicatin g that the inhibition of CYP1A2 was not related to metabolic activity of the CYP1A2 enzyme on serotonin or tryptamine. The CYP1A2 enzyme is expressed in brain and is involved in the metabolism of psychoactive d rugs. Therefore, the fact that endogenous compounds could modulate the CYP1A2 activity suggests that local activity of brain CYP1A2 might be susceptible to local regulatory mechanisms. This may have important c linical implications, one of them being that CYP1A2 activity in brain tissue might correlate poorly with that of liver, as observed in vivo. In addition, the influence of indoleamines on CYP1A2 activity might b e partly responsible for a number of associations of CYP1A2 activity w ith nutritional and environmental factors, Pharmacogenetics 8:251-258 (C) 1998 Lippincott-Raven Publishers.