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Polycyclic aromatic hydrocarbon‐inducible DNA adducts: Evidence by 32 P‐postlabeling and use of knockout mice for Ah receptor‐independent mechanisms of metabolic activation in vivo
Author(s) -
Kondraganti Sudha R.,
FernandezSalguero Pedro,
Gonzalez Frank J.,
Ramos Kenneth S.,
Jiang Weiwu,
Moorthy Bhagavatula
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10784
Subject(s) - cyp1b1 , carcinogen , aryl hydrocarbon receptor , cyp1a2 , cytochrome p450 , chemistry , dna damage , carcinogenesis , dna , dna adduct , microbiology and biotechnology , biochemistry , adduct , enzyme , biology , gene , transcription factor , organic chemistry
There is significant human exposure to polycyclic aromatic hydrocarbons (PAHs), many of which are potent carcinogens in laboratory animals and are suspected human carcinogens. The PAHs are bioactivated by cytochrome P450 (CYP)1A1/1B1 enzymes to reactive intermediates that bind to DNA, a critical step in the initiation of carcinogenesis. The Ah receptor (AHR) plays a critical role in the induction of CYP1 enzymes ( i.e. , CYP1A1, 1A2 and 1B1) by PAHs such as benzo[ a ]pyrene (BP) and 3‐methylcholanthrene (MC). In our investigation, we tested the hypothesis that AHR‐null animals are less susceptible to PAH‐induced DNA adduct formation than wild‐type animals. Wild‐type [AHR (+/+)] mice or mice lacking the gene for the AHR were treated with a single dose (100 μmol/kg) of BP or MC, and hepatic DNA adducts were analyzed by 32 P‐postlabeling. BP induced multiple hepatic DNA adducts in wild‐type as well as AHR‐null animals, suggesting the existence of AHR‐independent mechanisms for BP metabolic activation. On the other hand, DNA adduct formation was markedly suppressed in AHR‐null animals exposed to MC, although the major MC‐DNA adduct was produced in these animals. Hepatic activities and apoprotein contents of 7‐ethoxyresorufin O‐deethylase (EROD) (CYP1A1) and 7‐methoxyresorufin O‐demethylase (MROD) (CYP1A2) activities were markedly induced by BP and MC in the wild‐type, but not, in AHR‐null animals. CYP1B1 expression was also induced, albeit to a lesser extent by the PAH MC, but not BP, in the wild‐type animals. In conclusion, these results demonstrate the existence of AHR‐ and CYP1A1‐independent mechanisms of PAH metabolic activation in mouse liver, a phenomenon that may have important implications for PAH‐mediated carcinogenesis. © 2002 Wiley‐Liss, Inc.