Siest G, Jeannesson E, Berrahmoune H, Maumus S, Marteau J-B, Mohr S, Visvikis S
Université Henri Poincaré, INSERM U525, Nancy I, Faculté de Pharmacie, 30 rue Lionnois, 54000 Nancy, France.
Pharmacogenomics. 2004 Oct;5(7):779-802. doi: 10.1517/14622416.5.7.779.
There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.
共有17类药物用于治疗多种心血管疾病。我们提出了一种心血管治疗领域的综合药物基因组学方法，该方法考虑以下五个变异来源：药代动力学遗传学、药效学（药物靶点）遗传学、与特定病理及其相应药物治疗相关的遗传学、生理调节遗传学以及环境-基因相互作用。文中给出了参与I期（细胞色素P450）和II期（结合酶）药物代谢酶以及III期药物转运体的药代动力学遗传学实例。用于解释药效学遗传学的实例是糖蛋白IIIa以及对阿司匹林抗血小板作用的反应。与特定病理及其相应药物治疗相关的遗传学以ADRB1、ACE、CETP和APOE以及代谢综合征中的药物反应为例进行说明。文中给出了细胞色素P450、APOE和ADRB2与种族、年龄和性别的关系实例，以描述生理调节遗传学。最后，以CYP7A1以及饮食对血浆脂质水平的影响，和APOE以及吸烟在心血管疾病中的影响为例来说明环境-基因相互作用。我们使用心血管药物与基因多态性相关的实例来说明这种五层方法。
