Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine

被引:50
作者
He, Zhi-Xu [1 ,2 ]
Chen, Xiao-Wu [3 ]
Zhou, Zhi-Wei [4 ]
Zhou, Shu-Feng [1 ,2 ,4 ]
机构
[1] Guizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
[2] Guizhou Med Univ, Sino US Joint Lab Med Sci, Guiyang, Guizhou, Peoples R China
[3] Southern Med Univ, Dept Gen Surg, Peoples Hosp Shunde 1, Foshan, Guangdong, Peoples R China
[4] Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL USA
关键词
CYP2D6; regulation; HNF-4; inducer; inhibitor; GWAS; ST-JOHNS-WORT; DRUG-METABOLIZING-ENZYMES; GENOME-WIDE ASSOCIATION; HEPATITIS-C VIRUS; FARNESOID X RECEPTOR; MODIFICATION-SPECIFIC PROTEOMICS; HETERODIMER PARTNER INTERACTS; HEPATOCYTE NUCLEAR FACTOR-4; MESSENGER-RNA EXPRESSION; CHRONIC-RENAL-FAILURE;
D O I
10.3109/03602532.2015.1101131
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4 binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.
引用
收藏
页码:470 / 519
页数:50
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