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 microM 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 [32P]-dioxin responsive element in CL3 cells, but not in A427 cells. This study demonstrated that variation in AhR-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.
Chang
K W
KW
Institute of Toxicology, Chung-Shan Medical and Dental College, Taichung, Taiwan, ROC.
Lee
H
H
Wang
H J
HJ
Chen
S Y
SY
Lin
P
P
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism*; D004268:DNA-Binding Proteins; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D014157:Transcription Factors / Q000032:analysis; D014407:Tumor Cells, Cultured
C497396:ARNT protein, human; D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1