Differential response to benzo[a]pyrene in human lung adenocarcinoma cell lines: The absence of aryl hydrocarbon receptor activation

Benzo[a]pyrene (B[a]P) has been shown to produce DNA adducts and to initiate pulmonary carcinogenesis in animals. We observed differential susceptibility to B[a]P in two human lung adenocarcinoma cell lines, A427 and CL3. DNA adducts were induced by B[a]P treatment in CL3 cells, however, A427 cells were much less responsive to B[a]P treatment. Cytochrome P450 1A1 (CYP1A1) is involved in bioactivation of B[a]P in nonhepatic tissues. Cotreatment with alpha-naphthoflavone, a CYP1A1 inhibitor, abolished DNA adduct formation. by B[a]P in CL3 cells. Nevertheless, CYP1A1 inducer beta-naphthoflavone, enhanced DNA adduct formation by B[a]P in both A427 and CL3 cells. Both enzyme activity and mRNA levels of CYP1A1 were highly induced by 1 or 10 mu M B[a]P treatment for 24 hr in CL3 cells but not in A427 cells. Protein levels of AhR and aryl:hydrocarbon receptor nuclear translocator (Arnt) were similar in A427 and CL3 Cells before B[a]P treatment. However, B[a]P induced a retarded band with the [P-32]-dioxin responsive element in CL3 cells, but not in A427 cells. This study demonstrated that variation in ANI mediated CYP1A1 induction contributes to differential susceptibility to B[a]P-DNA adduct formation in human lung cells. Since AhR and/or Arnt function is impaired in A427 cells, this cell line offers a model for investigating the repression mechanisms of CYP1A1 induction by B[a]P in lung cells.