Shah Rashmi R, Smith Robert L
Rashmi Shah Consultancy Ltd., 8 Birchdale, Gerrards Cross, Buckinghamshire, United Kingdom (R.R.S.); and Department of Surgery and Cancer, Faculty of Medicine, Imperial College, South Kensington campus, London, United Kingdom (R.L.S.)
Rashmi Shah Consultancy Ltd., 8 Birchdale, Gerrards Cross, Buckinghamshire, United Kingdom (R.R.S.); and Department of Surgery and Cancer, Faculty of Medicine, Imperial College, South Kensington campus, London, United Kingdom (R.L.S.).
Drug Metab Dispos. 2015 Mar;43(3):400-10. doi: 10.1124/dmd.114.061093. Epub 2014 Dec 17.
Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.
表型转化可使药物的基因型广泛代谢者（EMs）暂时转变为表型慢代谢者（PMs），临床反应可能随之发生相应变化。这种现象通常是由联合使用抑制某些药物代谢酶（DMEs）的药物引起的，细胞色素P450家族的酶尤其如此。过去二十年收集的非临床证据也有力地表明，炎症期间释放的一些促炎细胞因子水平升高与药物代谢下调有关，尤其是P450家族的某些DMEs，从而可能导致暂时的表型转化。临床上，在与细胞因子升高相关的炎症性疾病中，如人类免疫缺陷病毒感染、癌症和肝病，已记录到NAT2、CYP2C19和CYP2D6的表型转化。其他炎症性疾病导致表型转化的可能性尚未研究，但实验和临床轶事证据也支持感染诱导的CYP1A2、CYP3A4和CYP2C9下调。总体而言，证据支持这样一种假设，即某些与促炎细胞因子升高相关的炎症性疾病可能导致某些DMEs的表型转化。由于与促炎细胞因子水平升高相关的炎症性疾病非常普遍，基因型EM患者转变为暂时的表型PMs可能比预期的更频繁。由于药物药代动力学，进而临床反应，受DME表型而非基因型本身的影响，表型转化（无论其原因如何）可能对以基因型为重点的临床结局关联研究的分析和解释产生重大影响。仅关注基因型可能会遗漏临床结局与DME表型之间的重要关联，从而危及个性化医疗的未来前景。
