Role of Cytochrome P450 3A4 in Cancer Drug Resistance: Challenges and Opportunities.

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Current drug metabolism Pub Date : 2024-01-01 DOI:10.2174/0113892002312369240703102215

Swaroop Kumar Pandey, Sona Verma, Shobha Upreti, Anuja Mishra, Neha Yadav, Hemlata Dwivedi-Agnihotri

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Abstract

One of the biggest obstacles to the treatment of diseases, particularly serious conditions like cancer, is therapeutic resistance. The process of drug resistance is influenced by a number of important variables, including MDR genes, drug efflux, low-quality medications, inadequate dosage, etc. Drug resistance must be addressed, and new combinations based on the pharmacokinetics/pharmacodynamics (PK-PD) characteristics of the partner pharmaceuticals must be developed in order to extend the half-lives of already available medications. The primary mechanism of drug elimination is hepatic biotransformation of medicines by cytochrome P450 (CYP) enzymes; of these CYPs, CYP3A4 makes up 30-40% of all known cytochromes that metabolize medications. Induction or inhibition of CYP3A4-mediated metabolism affects the pharmacokinetics of most anticancer drugs, but these details are not fully understood and highlighted because of the complexity of tumor microenvironments and various influencing patient related factors. The involvement of CYPs, particularly CYP3A4 and other drug-metabolizing enzymes, in cancer medication resistance will be covered in the current review.

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细胞色素 P450 3A4 在癌症耐药性中的作用：挑战与机遇。

治疗疾病，尤其是癌症等严重疾病的最大障碍之一是耐药性。耐药性的产生过程受许多重要变量的影响，包括 MDR 基因、药物外流、劣质药物、剂量不足等。必须解决耐药性问题，并根据合作药物的药代动力学/药效学（PK-PD）特性开发新的组合，以延长现有药物的半衰期。药物消除的主要机制是细胞色素 P450（CYP）酶对药物的肝脏生物转化；在这些 CYP 中，CYP3A4 占所有已知代谢药物的细胞色素的 30-40%。诱导或抑制 CYP3A4 介导的代谢会影响大多数抗癌药物的药代动力学，但由于肿瘤微环境的复杂性和各种与患者相关的影响因素，这些细节尚未得到充分了解和强调。本综述将介绍 CYPs，特别是 CYP3A4 和其他药物代谢酶参与癌症耐药性的情况。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.