Dept. of Animal Biology and the Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Genet Metab. 2010 Jan;99(1):90-7. doi: 10.1016/j.ymgme.2009.08.009.
Human cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of approximately 20% of drugs in common clinical use. The CYP2D6 gene locus is highly polymorphic. Many of the polymorphisms have been shown to be clinically relevant and can account for inter-individual differences in the metabolism of specific drugs. In addition to the established sources of variability in CYP2D6-dependent drug metabolism, a recent study in our laboratory identified CYP2D6 in the mitochondria of human liver samples and found that it is metabolically active in this novel location. In the present study we show that mutations are present in the targeting signal region of CYP2D6 that may help to account for the inter-individual variability that was observed previously in the level of the mitochondrial enzyme in human liver samples. These mutations were identified within the ER targeting domain, the proline-rich domain as well as the putative protein kinase A (PKA) and protein kinase C (PKC)-specific phosphorylation sites. In vitro studies demonstrate that the mutations identified in the targeting signals affect the efficiency of mitochondrial targeting of CYP2D6. Since the mitochondrial enzyme has been shown to be active in drug metabolism, this pharmacogenetic variation could play a role in modulating the response of an individual to drug therapy.
人类细胞色素 P450 2D6（CYP2D6）负责大约 20%常用临床药物的代谢。CYP2D6 基因座高度多态性。许多已被证明具有临床相关性的多态性可导致特定药物代谢的个体间差异。除了 CYP2D6 依赖性药物代谢的既定变异来源外，我们实验室最近的一项研究在人肝样本的线粒体中鉴定出 CYP2D6，并发现其在该新位置具有代谢活性。在本研究中，我们表明 CYP2D6 的靶向信号区域存在突变，这可能有助于解释先前在人肝样本中线粒体酶水平观察到的个体间变异性。这些突变位于 ER 靶向结构域、富含脯氨酸的结构域以及假定的蛋白激酶 A（PKA）和蛋白激酶 C（PKC）特异性磷酸化位点内。体外研究表明，靶向信号中鉴定出的突变会影响 CYP2D6 向线粒体的靶向效率。由于已证明线粒体酶在药物代谢中具有活性，这种药物遗传学变异可能在调节个体对药物治疗的反应中发挥作用。
