Agúndez J A, Gallardo L, Martínez C, Gervasini G, Benítez J
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
Pharmacogenetics. 1998 Jun;8(3):251-8.
Recent evidence supports a role for the CYP2D6 enzyme in the metabolism of tryptamine. Because of the partial overlapping between substrate and inhibitor specificities that characterize some cytochrome P450 enzymes, these finding 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, precursors and metabolites on the cytochrome P450 1A2 (CYP1A2) enzyme activity was studied in human liver microsomes. Two indoleamines, serotonin and tryptamine, showed a competitive inhibitory effect on the high-affinity component of the phenacetin O-de-ethylase activity. Both substances induced an inhibition of 100% of the activity, with Ki values of 35 and 45 microns for serotonin and tryptamine, respectively. The inhibitors did not affect the microsomal NADPH-reductase activity. Other substances, which were either poor or partial inhibitors, were dopamine, L-tyrosine, tryptophol, 5-hydroxytryptophol, adrenaline, indole-3-acetaldehyde, 5-hydroxytryptophan, noradrenaline, vanillylmandelic acid, indole-3-acetic acid, dihydroxyphenylacetic acid, and homovanillic acid. L-tryptophan, dihydroxyphenylalanine and 5-hyroxyindole acetic acid induced very low or no inhibitory effect. Tryptamine and serotonin metabolism in human liver microsomes was studied after inhibition of monoamine oxidase activity with the unspecific MAO inhibitor pargyline. Both serotonin and tryptamine were metabolized in human liver microsomes. However, the metabolism of both indoleamines was not significantly inhibited with the CYP1A2-specific inhibitor furafylline, thus indicating 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 drugs. 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 clinical 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 be partly responsible for a number of associations of CYP1A2 activity with nutritional and environmental factors.
最近的证据支持细胞色素P450 2D6酶在色胺代谢中发挥作用。由于某些细胞色素P450酶的底物和抑制剂特异性存在部分重叠，这些发现增加了其他细胞色素P450酶可能受内源性化合物调节的可能性。在本研究中，研究了17种神经递质、前体和代谢产物对人肝微粒体中细胞色素P450 1A2（CYP1A2）酶活性的调节作用。两种吲哚胺，血清素和色胺，对非那西丁O-脱乙基酶活性的高亲和力组分表现出竞争性抑制作用。两种物质均导致100%的活性受到抑制，血清素和色胺的Ki值分别为35和45微摩尔。这些抑制剂不影响微粒体NADPH还原酶活性。其他物质，要么是弱抑制剂，要么是部分抑制剂，包括多巴胺、L-酪氨酸、色醇、5-羟基色醇、肾上腺素、吲哚-3-乙醛、5-羟基色氨酸、去甲肾上腺素、香草扁桃酸、吲哚-3-乙酸、二羟基苯乙酸和高香草酸。L-色氨酸、二羟基苯丙氨酸和5-羟基吲哚乙酸诱导的抑制作用非常低或没有抑制作用。在用非特异性单胺氧化酶抑制剂帕吉林抑制单胺氧化酶活性后，研究了人肝微粒体中的色胺和血清素代谢。血清素和色胺在人肝微粒体中均有代谢。然而，两种吲哚胺的代谢并未被CYP1A2特异性抑制剂呋拉茶碱显著抑制，因此表明CYP1A2活性的抑制与CYP1A2酶对血清素或色胺的代谢活性无关。CYP1A2酶在大脑中表达，并参与精神活性药物的代谢。因此，内源性化合物可以调节CYP1A2活性这一事实表明，大脑中CYP1A2的局部活性可能易受局部调节机制的影响。这可能具有重要的临床意义，其中之一是，正如在体内观察到的那样，脑组织中的CYP1A2活性可能与肝脏中的活性相关性较差。此外，吲哚胺对CYP1A2活性的影响可能部分解释了CYP1A2活性与营养和环境因素之间的一些关联。
