Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy

SIMPLE SUMMARY: The effectiveness and safety of the anti-cancer agent doxorubicin (anthracycline group medicine) depend on the metabolism and retention of the drug in the human organism. Polymorphism of cytochrome p450 (CYP)-encoding genes and detoxifying enzymes such as CYP3A4 and CYP2D6 were found responsible for variations in the doxorubicin metabolism. Transmembrane transporters such as p-glycoproteins were reported to be involved in cancer tissue retention of doxorubicin. ATP-binding cassette (ABC) family members, including ABCB1 transporters (also known as Multi-Drug Resistance 1 (MDR1)) proteins, were determined to pump out doxorubicin from breast cancer cells, therefore reducing the drug effectiveness. This study critically discusses the latest data about the role of CYP3A4, CYP2D6, and ABCB1 gene polymorphism in the regulation of doxorubicin’s effects in breast cancer patients. The assessment of genetic differences in the expression of doxorubicin metabolizing and transporting enzymes should be explored for the development of personalized medical treatment of breast cancer patients. ABSTRACT: Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin’s anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.