Polymorphisms characteristics of enzymes (CYP2C9,CYP2C8,ALDH1A, ALDH3A1) in cyclophosphamide metabolic pathway, Siklofosfamid metabolik yolatinda yer alan en zimlerin(CYP2C9,CYP2C8,ALDH1A, ALDH3A1) polimorfik ozellikleri

Abstract

The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Cyclophosphamide has a relatively narrow therapeutic index, and side effects. Toxicity and response to cyclophosphamide is quite variable. Polymorphisms of the metabolizing enzymes may affect the pharmacokinetic, toxicity and response to cyclophosphamide based therapy. Blood samples were collected from 10 pediatric patients with solid tumors who were receiving cyclophosphamide chemotherapy in the Dokuz Eylul University School of Medicine Department of Pediatric Oncology. Genomic DNA was extracted from peripheral blood. The genes coding the enzymes in the metabolic processes of the cyclophosphamide (CYP2C9, CYP2C8, ALDH1A and ALDH3A1) were analyzed with the new genaration Sequenom MassARRAY Analyzer 4 in terms of single nucleotid polymorphizm. The observed frequencies of the variant alleles CYP2C9(*2*3tag), CYP2C9-50298A>T, CYP2C9-50196C>T, rs10509680 G>T, rs 4086116 C>T, rs1934968 G > A, rs1058932C>T, CYP2C8*3,rs 11572177 A>G, rs 17110453A>C, ALDH3A1*2 were 60%, 40%, 10%, 30%, 20%, 20%, 20%, 30%, 60%, 10%, 40% carrier respectively and also 10% homozygote (mutant) for CYP2C8*3 allele and ALDH1A1*2 allele.Mutation in ALDH1A1*2 allele decrease 4hydroxycyclophosphamide concentration in the metabolic pathway. Recognition of the widespread presence of pharmacoethnicity in cancer therapeutics is important in worldwide drug discovery and development. There are many studies in this field but there isn't much data from Turkish population. Our study is a preliminary work . Determination of selected enzymes genotypes may be valuable for predicting the risk of cyclophosphamide toxicity. The association of these genotypes with toxicity and ethnicity needs further population base validations