Introduction: Genetic polymorphisms refer to variations in DNA sequences among individuals, which can influence the cell's response to drugs. These variations can manifest in various forms, including single nucleotide polymorphisms (SNPs) or copy number variations (CNVs). Such polymorphisms play a crucial role in determining individual reactions to drugs and their tolerability. Pharmacogenetics is a branch of science that studies the impact of individual genetic differences on drug responses. The primary goal of this field is to identify genetic polymorphisms that can explain different drug reactions and thereby aid in the development of personalized therapies. These genetic variations can affect the pharmacokinetics and pharmacodynamics of drugs, leading to differences in drug metabolism, absorption, distribution, and excretion. In other words, genetic differences can cause a drug to be effective in some individuals while being ineffective or even causing serious side effects in others.
A significant example involves the CYP450 family genes, which are essential in the metabolism of many drugs. Polymorphisms in CYP2C19 and CYP2C9 genes can greatly influence the metabolism of drugs such as clopidogrel and warfarin (anticoagulants). For instance, individuals with inactive alleles in the CYP2C19 gene may not respond to clopidogrel and might require an alternative medication. As mentioned, genetic polymorphisms can also increase or decrease drug toxicity. For example, in cancer treatments, polymorphisms in genes related to drug metabolism can lead to increased toxicity or drug resistance. Recent studies have shown that polymorphisms in CYP3A4 and CYP3A5 genes can significantly affect the response to atorvastatin (a drug for preventing heart disease), which may lead to changes in treatment efficacy.
Methods: This review article compiles and discusses research on genetic polymorphisms and their role in drug toxicity . Information was sourced from databases such as PubMed , NCBI, MDPI and Google Scholar.
Results: Genetic polymorphisms in drug-metabolizing enzymes can also have significant impacts on drug responses, efficacy, and toxicity. For instance, enzymes from the cytochrome P450 family, such as CYP2C9 and CYP2C19 (which play key roles in the metabolism of various drugs, including warfarin and clopidogrel), and CYP3A4 and CYP3A5 (involved in the metabolism of many drugs, including statins and some anticancer drugs). Drug transporter proteins play a vital role in regulating the absorption, distribution, and excretion of drugs. Genetic polymorphisms in these proteins can significantly affect the pharmacokinetics and pharmacodynamics of drugs. Identifying and studying these polymorphisms is crucial for improving personalized treatments and reducing drug side effects. Some of these proteins include: SLCO1B1/OATP1B1 (which plays a key role in drug transport into the liver), ABCB1/MDR1 (P-glycoprotein, which is involved in drug efflux from cells and preventing their accumulation in sensitive tissues), ABCG2/BCRP (involved in drug and metabolite efflux from cells), and ABCC2/MRP2 (important in the biliary excretion of drugs and their metabolites).
Conclusion: Understanding and identifying genetic polymorphisms through genetic testing can enhance personalized treatments, increase treatment efficacy, and reduce drug side effects. This information can help physicians in more precise drug dosing and in choosing more appropriate medications for patients. Further research in this area can lead to the identification of new genetic markers associated with drug toxicity and the development of personalized therapeutic approaches. Such research not only helps improve patient treatment management and safety but can also reduce the costs associated with unsuccessful treatments and adverse side effects.
Keywords: Genetic polymorphisms, Drug response, Drug metabolism, Drug toxicity, Drug resistance