Interaction of CYP3A4, CYP3A5, CYP1A1 and CYP2B6 genes in the development of organotoxic effects of chemotherapy in patients with Hodgkin's lymphoma

Relevance . Modern chemotherapy for Hodgkin lymphoma (HL) achieves long-term remissions in 80–85 % of patients. Some patients develop drugrelated toxicity. Polymorphisms in drug-metabolizing cytochrome P450 (CYP) genes contribute to individual differences in the therapeutic and side effects of chemotherapy. In this regard, chemotherapy for HL in Russia has not been sufficiently studied. Objective. To study the relationship between polymorphic variants of CYP3A4, CYP3A5, CYP1A1 , and CYP2B6 and the development of organotoxic effects of HL therapy. Methods. Polymorphic variants CYP3A4 (rs4987161, rs28371759, rs2740574), CYP3A5 rs776746, CYP1A1 (rs1048943, rs4646421), and CYP2B6 (rs2279343) were determined by polymerase chain reaction with real-time detection. Their association with organotoxic complications was assessed by odds ratio and using Multifactorial Dimensionality Reduction (MDR). Results. MDR analysis showed the significance of polymorphic variants of four genes for hepatotoxicity with the main contribution of CYP1A1 rs464642. Synergism was observed for CYP1A1 rs4646421 and CYP2B6 rs227934 and CYP2B6 rs227934 and CYP3A5 rs776746 , and antagonism was observed for CYP1A1 rs4646421 and CYP3A5 rs776746 . The main contributor to cardiotoxicity was CYP2B6 rs227934 , which showed synergy with both CYP1A1 variants. The main contribution to the development of anemia was made by CYP3A5 rs776746 , for which synergism with CYP1A1 rs104894 was noted; for leukopenia — CYP1A1 rs464642 ; for granulocytopenia — CYP2B6 rs227934 , antagonism with CYP1A1 variants was noted; for thrombocytopenia — CYP3A4 rs2740574 , antagonism with CYP3A5 rs776746 was observed. Conclusion. The results show that different combinations of polymorphic variants of CYP genes are associated with different types of organotoxicity and that different genes make a major contribution.