Niwa Toshiro, Murayama Norie, Umeyama Hiromi, Shimizu Makiko, Yamazaki Hiroshi
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Drug Metab Lett. 2011 Aug;5(3):216-9. doi: 10.2174/187231211796905026.
Dietary tyramine is associated with hypertensive crises because of its ability to induce the release of catecholamines. The roles of monoamine oxidase (MAO); flavin-containing monooxygenase (FMO); and cytochrome P450 2D6 (CYP2D6) were studied in terms of the enzymatic elimination of tyramine in vitro at a substrate concentration of 1.0 µM; which is relevant to in vivo serum concentrations. Tyramine elimination by human liver supernatant fractions was decreased by ˜70% in the absence of NADPH. Pargyline; an MAO inhibitor; decreased tyramine elimination rates by ˜30%. Among recombinant P450 and FMO enzymes; CYP2D6 had a high activity in terms of tyramine elimination. Tyramine elimination rates were inhibited by quinidine and significantly correlated with bufuralol 1'-hydroxylation activities (a CYP2D6 marker). Liver microsomes genotyped for CYP2D6*10/10 and CYP2D64/4 showed low and undetectable activities; respectively; compared with the wild-type CYP2D61/*1. The present results suggest that tyramine is eliminated mainly by polymorphic CYP2D6. Tyramine toxicity resulting from differences in individual metabolic elimination is thus genetically determined.
膳食酪胺与高血压危象有关，因为它能够诱导儿茶酚胺的释放。在底物浓度为1.0 μM（这与体内血清浓度相关）的情况下，研究了单胺氧化酶（MAO）、含黄素单加氧酶（FMO）和细胞色素P450 2D6（CYP2D6）在体外对酪胺的酶促消除作用。在没有NADPH的情况下，人肝上清液组分对酪胺的消除作用降低了约70%。MAO抑制剂帕吉林使酪胺消除率降低了约30%。在重组P450和FMO酶中，CYP2D6在酪胺消除方面具有高活性。酪胺消除率受到奎尼丁的抑制，并且与布非洛尔1'-羟化活性（一种CYP2D6标志物）显著相关。对CYP2D6*10/10和CYP2D64/4进行基因分型的肝微粒体分别显示出低活性和未检测到的活性，与野生型CYP2D61/*1相比。目前的结果表明，酪胺主要通过多态性CYP2D6消除。因此，个体代谢消除差异导致的酪胺毒性是由基因决定的。
