Phase I and Phase II enzyme polymorphisms and childhood cancer

Childhood cancers continue to be challenging clinical entities whose etiology, demographic characteristics, clinical progression, treatment efficacy, and outcomes remain incompletely understood. Research suggests that multiple environmental and genetic factors may play crucial roles in the pathophysiology of many of these malignancies. Recent attention has been directed to the role of carcinogen metabolizing enzymes in the etiology and progression of cancer in both adults and children due to their multitude of polymorphic variants and their intimate interaction with environmental factors. In particular, xenobiotic metabolizing enzymes (XME), which are intimately involved in the activation and deactivation of many environmental carcinogens, have become an area of significant interest. Traditionally, these enzymes have been classified into either phase I or phase II enzymes depending on their substrates, activity, and occasionally based on their sequence in the metabolic pathways, and have been demonstrated to have numerous polymorphic variants. Phase I enzymes predominantly consist of cytochrome enzymes responsible for mixed function oxidase activity, whereas phase II enzymes are frequently conjugation reactions necessary for drug metabolism or the further metabolism of phase I enzyme products. Current research has discovered numerous interactions between polymorphisms in these enzymes and changes in cancer susceptibility, treatment efficacy, and clinical outcomes in childhood cancer. Furthermore, studies of polymorphisms in these enzymes have demonstrated to have synergistic/antagonistic interactions with other XME polymorphisms and demonstrate variable influences on disease pathophysiology depending on the patient's ethnic background and environmental milieu. Continuing research on the role of polymorphisms in phase I and phase II enzymes will likely further elucidate the intimate role of these polymorphisms with environmental factors in the etiology of childhood cancer.