[haematologica reports] 2006;2(15):46-48 MARIA TERESA VOSO FRANCESCO D’ALO’ GIUSEPPE LEONE Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italy Detoxification enzyme polymorphisms as risk factors fo t-AML T odate,therapy-relatedmyelodys- plastic syndromes/acute Myeloid Leukemias (t-MDS/ AML) represent the main long-term adverseeffectofcancertreatment.The identificationofnewprognosticfactors hasraisedthequestionwhetherreduc- ing treatment intensity in good prog- nosispatientsmaysavethemfromlong term-toxicity, without impairing response rates. Although the genotoxic effects of ionizing radiation and chemotherapic drugsplaythecentralroleinpathogen- esis of t-MDS/AML, individual suscep- tibility factors can help to identify patientsatincreasedrisk.Inparticular, genetic polymorphisms in genes codi- fying for drug metabolizing and DNA repairenzymesmayinterferewithcor- rectworkingofphysiologicalprocesses that protect cells against drug- and radiation-induced genomic damage and may contribute to explain why some patients develop secondary neo- plasias and others do not. Drug or xenobiotic metabolizing enzymes (DME) include several enzy- matic families involved in the metabo- lism, biotransformation, and detoxifi- cationofxenobioticsandforeigncom- pounds.Theydisplayahighdegreeof polymorphism in the general popula- tion.TwomainDMAclasseshavebeen identified,namedPhaseIandPhaseII enzymes, respectively. Phase I DMEs primarily consist of the cytochrome P450 (CYP) superfamily, which is found in abundance in the liver, gas- trointestinal tract, lung and kidneys, andconsistsoffamiliesandsubfamilies classified based on their amino acid sequence identities or similarities. Theseenzymesparticipatetofirststeps of detoxification from xenobiotic and arefrequentlyresponsibleoftheiracti- vation to reactive intermediates that canformadductswithDNA,leadingto its damage. 1 The Phase II drug metabolizing or conjugating enzymes consist of many superfamily of enzymes, including sul- fotransferases, glucuronosyltransferas- es,NAD(P)H:quinoneoxidoreductase (NQO), epoxide hydrolases (EPH), glutathione S-transferases (GST) and N-acetyltransferases(NAT).Generally, Phase II affect detoxification and ulti- mately excretion and elimination of many drugs and xenobiotics that con- tainhydroxyl(OH)functionalgroups, highly reactive, either present on the parent molecules and/or after bio- transformationbythePhaseIenzymes. Forinstance,reactiveelectrophilesare typically conjugated with glutathione (GSH)byvariousGSTs,andwhenGSH levels in the cells are attenuated, DNA and other cellular constituents are at high risk of damage. 1 SeveralPhaseIandPhaseIIenzymes are involved in detoxification of chemotherapic agents and their poly- morphismshavebeenoftencorrelated to modified risk of t-MDS/AML. Epipodophyllotoxins, as well as cyclophosphamide, ifosphamide, vin- blastine, and vindesine are substrates for metabolism by CYP3A, the most abundant component of the CYP sys- tem in the human liver. 2 A variant in the 5' promoter region of the CYP3A4 gene (CYP3A4-V), associated to reduced intracellular enzyme level, decrease production of the epipodophyllotoxin catechol metabo- lite, which is the precursor of the potentially DNA-damaging quinone. Accordingly, Felix et al showed that 19% de novo and only 3% treatment- relatedleukemiascarriedtheCYP3A4- V, and that the variant was absent in patientswithMLLgenetranslocation.3 ThesedatawereconfirmedbyRund et al. Individuals carrying the CYP3A4- wild type genotype may have increased productionofpotentiallyDNA-damag- ing reactive intermediates and are at Third International Symposium on Secondary Leukemias, Rome, 3-4 November 2006 |46| haematologica reports 2006; 2(issue 15):November 2006