Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA.
Pharmacotherapy. 2010 Feb;30(2):195-209. doi: 10.1592/phco.30.2.195.
The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.
钙调神经磷酸酶抑制剂-环孢素和他克莫司是实体器官移植中免疫抑制治疗的主要药物。这些药物会产生严重的药物不良反应（ADEs），如肾毒性、移植后糖尿病和高血压。有大量证据表明，2 型糖尿病、高血压和肾衰竭的发展可能与特定的 DNA 基因型有关。在这篇综述中，比较了与这些疾病过程发展相关的基因与钙调神经磷酸酶抑制剂诱导的 ADEs 相关的基因。肾素-血管紧张素系统基因、细胞因子编码基因和纤溶酶原激活物抑制剂 1 基因与钙调神经磷酸酶抑制剂诱导的肾毒性以及肾衰竭的发展有关。许多基因与糖尿病的发生有关，包括维生素 D 受体基因（VDR）、肝细胞核因子基因（HNF）、转录因子 7 样 2 基因（TCF7L2）、血管紧张素转换酶基因（ACE）、细胞因子、过氧化物酶体增殖物激活受体γ基因（PPARG）等。研究表明，VDR、PPARG、HNF1A 和腺苷 5'-三磷酸结合盒 ABCC8（编码磺脲类受体）基因与钙调神经磷酸酶抑制剂诱导的糖尿病有关。编码血管紧张素转换酶、内皮型一氧化氮合酶和细胞色素 P450 3A 同工酶的基因与高血压的发生以及钙调神经磷酸酶抑制剂诱导的高血压有关。疾病状态的遗传研究可以为深入了解 ADEs 的遗传基础提供基础。基因多态性与疾病的发生和相应的疾病样 ADEs 有关。与疾病相关的基因提供了探索 ADEs 的候选基因，并可能为评估发生严重钙调神经磷酸酶抑制剂相关 ADEs 的风险以及制定预防策略提供基因组生物标志物。
