Impaired dacarbazine activation and 7-ethoxyresorufin deethylation in vitro by polymorphic variants of CYP1A1 and CYP1A2: Implications for cancer therapy

Objectives To extend our understanding of how interindividual variability mediates the efficacy of cancer treatment. Materials and methods The kinetics of dacarbazine (DTIC) N-demethylation by the most frequent polymorphic variants of CYP1A1 (T461N, I462V) and CYP1A2 (F186L, D348N, I386F, R431W, R456H) were characterized, along with kinetic parameters for the O-deethylation of the prototypic CYP1A substrate 7-ethoxyresorufin, using recombinant protein expression and high-performance liquid chromatographic techniques. Results A reduction of ∼30% in the catalytic efficiencies (measured as in-vitro intrinsic clearance, CL_int) was observed for DTIC N-demethylation by the two CYP1A1 variants relative to wild type. Although a modest increase in the CL_int value for DTIC N-demethylation was observed for the CYP1A2 D348N variant relative to the wild type, the CL_int for the F186L variant was reduced and the I386F, R431W, and R456H variants all showed loss of catalytic function. Conclusion Comparison of the kinetic data for DTIC N-demethylation and 7-ethoxyresorufin O-deethylation indicated that alterations in the kinetic parameters (K_m, V_max, CL_int) observed with each of the CYP1A1 and CYP1A2 polymorphic variants were substrate dependent. These data indicate that cancer patients treated with DTIC who possess any of the CYP1A1-T461N and I462V variants or the CYP1A2-F186L, D348N, I386F, R431W, and R456H variants are likely to have decreased prodrug activation, and hence may respond less favorably to DTIC treatment compared with individuals with wild-type CYP1A alleles.