Martínez C, Agúndez J A, Gervasini G, Martín R, Benítez J
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
Pharmacogenetics. 1997 Apr;7(2):85-93.
The fact that CYP2D6 is not only expressed in liver but also in brain and the clinical association of this cytochrome with Parkinson's disease suggests the possibility of existence of some endogenous substrate, and among these perhaps one or more neurotransmitters could be metabolized by CYP2D6. In this study we explored such a possibility by studying the modulation of CYP2D6 activity by several neurotransmitters. Our findings confirm the occurrence of a competitive inhibition of dextromethorphan O-demethylation in the presence of tryptamine, with a Ki value of 44.6 microM. Tryptamine was metabolized in human liver microsomes by an enzyme activity with a K(m) of 3.6 +/- 0.9 microM. Such activity is NADPH dependent and is inhibited by quinidine and CYP2D6-specific substrates. The product of the reaction is tryptophol. These results suggest that tryptamine may be an endogenous substrate of CYP2D6.
细胞色素P450 2D6（CYP2D6）不仅在肝脏中表达，也在大脑中表达，且这种细胞色素与帕金森病的临床关联提示存在某些内源性底物的可能性，其中或许有一个或多个神经递质可被CYP2D6代谢。在本研究中，我们通过研究几种神经递质对CYP2D6活性的调节来探索这种可能性。我们的研究结果证实，在色胺存在的情况下，右美沙芬O-去甲基化发生竞争性抑制，其抑制常数（Ki）值为44.6微摩尔。色胺在人肝微粒体中被一种酶活性代谢，该酶的米氏常数（K(m)）为3.6±0.9微摩尔。这种活性依赖于烟酰胺腺嘌呤二核苷酸磷酸（NADPH），并被奎尼丁和CYP2D6特异性底物抑制。反应产物为色醇。这些结果表明色胺可能是CYP2D6的内源性底物。
