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Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect

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Abstract

The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person’s response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes.

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Acknowledgments

Gera Narendra and Baddipadige Raju acknowledge the Indian Council of Medical Research, New Delhi for providing a Senior Research Fellowship; Sanction No. ISRM/12(10)/2019.

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  1. Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, 147002, Patiala, Punjab, India

    Gera Narendra, Shalki Choudhary, Baddipadige Raju, Himanshu Verma & Om Silakari

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Correspondence to Om Silakari.

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This work was supported by the Indian Council of Medical Research, New Delhi, grant number ISRM/12(10)/2019.

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GN: conceptualization and writing of the original manuscript, SC: manuscript editing, BR: editing and corrections, HV: manuscript editing, OS: supervision.

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Narendra, G., Choudhary, S., Raju, B. et al. Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect. Clin Pharmacokinet 61, 1495–1517 (2022). https://doi.org/10.1007/s40262-022-01174-7

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