PMID- 12455047
OWN - NLM
STAT- MEDLINE
DCOM- 20030106
LR  - 20220330
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 103
IP  - 1
DP  - 2003 Jan 1
TI  - Polycyclic aromatic hydrocarbon-inducible DNA adducts: evidence by 
      32P-postlabeling and use of knockout mice for Ah receptor-independent mechanisms 
      of metabolic activation in vivo.
PG  - 5-11
AB  - 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 micromol/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.
CI  - Copyright 2002 Wiley-Liss, Inc.
FAU - Kondraganti, Sudha R
AU  - Kondraganti SR
AD  - Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Fernandez-Salguero, Pedro
AU  - Fernandez-Salguero P
FAU - Gonzalez, Frank J
AU  - Gonzalez FJ
FAU - Ramos, Kenneth S
AU  - Ramos KS
FAU - Jiang, Weiwu
AU  - Jiang W
FAU - Moorthy, Bhagavatula
AU  - Moorthy B
LA  - eng
GR  - ES 09132/ES/NIEHS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (DNA Adducts)
RN  - 0 (Phosphorus Isotopes)
RN  - 0 (Polycyclic Aromatic Hydrocarbons)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (polycyclic aromatic hydrocarbons-DNA adduct)
RN  - 3417WMA06D (Benzo(a)pyrene)
RN  - 56-49-5 (Methylcholanthrene)
RN  - 9007-49-2 (DNA)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP1B1 protein, human)
RN  - EC 1.14.14.1 (Cyp1b1 protein, mouse)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1B1)
SB  - IM
MH  - Animals
MH  - Aryl Hydrocarbon Hydroxylases/*metabolism
MH  - Benzo(a)pyrene/toxicity
MH  - Cytochrome P-450 CYP1A1/*metabolism
MH  - Cytochrome P-450 CYP1A2/*metabolism
MH  - Cytochrome P-450 CYP1B1
MH  - DNA/*drug effects/metabolism
MH  - DNA Adducts/*metabolism
MH  - Enzyme Activation
MH  - Enzyme Induction
MH  - Homozygote
MH  - Isotope Labeling
MH  - Liver/*drug effects/enzymology
MH  - Male
MH  - Methylcholanthrene/toxicity
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microsomes, Liver/enzymology
MH  - Phosphorus Isotopes
MH  - Polycyclic Aromatic Hydrocarbons/*metabolism
MH  - Receptors, Aryl Hydrocarbon/*metabolism
EDAT- 2002/11/28 04:00
MHDA- 2003/01/08 04:00
CRDT- 2002/11/28 04:00
PHST- 2002/11/28 04:00 [pubmed]
PHST- 2003/01/08 04:00 [medline]
PHST- 2002/11/28 04:00 [entrez]
AID - 10.1002/ijc.10784 [doi]
PST - ppublish
SO  - Int J Cancer. 2003 Jan 1;103(1):5-11. doi: 10.1002/ijc.10784.