Open AccessAssociation of CYP 3 A 4 genotype with treatment-related leukemia
Author(s) -
Carolyn A. Felix,
A. H. C. Walker,
Beverly J. Lange,
Terence M. Williams,
Naomi J. Winick,
Nai Kong V. Cheung,
Brian D. Lovett,
Peter C. Nowell̀,
Ian A. Blair,
Timothy R. Rebbeck
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.22.13176
Subject(s) - cyp3a4 , chromosomal translocation , cyp3a , genotype , biology , leukemia , microbiology and biotechnology , gene , genetics , cancer research , pharmacology , cytochrome p450 , metabolism , biochemistry
Epipodophyllotoxins are associated with leukemias characterized by translocations of theMLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5′ promoter region of theCYP3A4 gene (CYP3A4-V ) that might alter the metabolism of anticancer drugs. We examined 99de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of theCYP3A4-V . In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried theCYP3A4-V (P = 0.026; Fisher’s Exact Test, FET). Nine of 42de novo leukemias withMLL gene translocations (21%), and 0 of 22 treatment-related leukemias withMLL gene translocations carried theCYP3A4-V (P = 0.016, FET). This relationship remained significant when 19 treatment-related leukemias withMLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42de novo cases (P = 0.026, FET). These data suggest that individuals withCYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. TheCYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.