PMID- 16696575
OWN - NLM
STAT- MEDLINE
DCOM- 20060707
LR  - 20211020
IS  - 0893-228X (Print)
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 19
IP  - 5
DP  - 2006 May
TI  - Polycyclic aromatic hydrocarbon (PAH) o-quinones produced by the 
      aldo-keto-reductases (AKRs) generate abasic sites, oxidized pyrimidines, and 
      8-oxo-dGuo via reactive oxygen species.
PG  - 719-28
AB  - Reactive and redox-active polycyclic aromatic hydrocarbon (PAH) o-quinones 
      produced by Aldo-Keto Reductases (AKRs) have the potential to cause depurinating 
      adducts leading to the formation of abasic sites and oxidative base lesions. The 
      aldehyde reactive probe (ARP) was used to detect these lesions in calf thymus DNA 
      treated with three PAH o-quinones (BP-7,8-dione, 7,12-DMBA-3,4-dione, and 
      BA-3,4-dione) in the absence and presence of redox-cycling conditions. In the 
      absence of redox-cycling, a modest amount of abasic sites were detected 
      indicating the formation of a low level of covalent o-quinone depurinating 
      adducts (>3.2 x 10(6) dNs). In the presence of NADPH and CuCl2, the three PAH 
      o-quinones increased the formation of abasic sites due to ROS-derived lesions 
      destabilizing the N-glycosidic bond. The predominant source of AP sites, however, 
      was revealed by coupling the assay with human 8-oxoguanine glycosylase (hOGG1) 
      treatment, showing that 8-oxo-dGuo was the major lesion caused by PAH o-quinones. 
      The levels of 8-oxo-dGuo formation were independently validated by HPLC-ECD 
      analysis. Apyrimidinic sites were also revealed by coupling the assay with 
      Escherichia coli (Endo III) treatment showing that oxidized pyrimidines were 
      formed, but to a lesser extent. Different mechanisms were responsible for the 
      formation of the oxidative lesions depending on whether Cu(II) or Fe(III) was 
      used in the redox-cycling conditions. In the presence of Cu(II)-mediated PAH 
      o-quinone redox-cycling, catalase completely suppressed the formation of the 
      lesions, but mannitol and sodium benzoate were without effect. By contrast, 
      sodium azide, which acts as a *OH and 1O2 scavenger, inhibited the formation of 
      all oxidative lesions, suggesting that the ROS responsible was 1O2. However, in 
      the presence of Fe(III)-mediated PAH o-quinone redox-cycling, the *OH radical 
      scavengers and sodium azide consistently attenuated their formation, indicating 
      that the ROS responsible was *OH.
FAU - Park, Jong-Heum
AU  - Park JH
AD  - Department of Pharmacology, University of Pennsylvania School of Medicine, 
      Philadelphia, Pennsylvania 19104-6084, USA.
FAU - Troxel, Andrea B
AU  - Troxel AB
FAU - Harvey, Ronald G
AU  - Harvey RG
FAU - Penning, Trevor M
AU  - Penning TM
LA  - eng
GR  - P01 CA092537-04/CA/NCI NIH HHS/United States
GR  - P01 CA092537/CA/NCI NIH HHS/United States
GR  - R01 CA039504/CA/NCI NIH HHS/United States
GR  - P30 ES013508/ES/NIEHS NIH HHS/United States
GR  - R01-CA-39504/CA/NCI NIH HHS/United States
GR  - R01 CA039504-20/CA/NCI NIH HHS/United States
GR  - P01-CA-092537/CA/NCI NIH HHS/United States
GR  - P30 ES013508-01A1/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Benz(a)Anthracenes)
RN  - 0 (Benzopyrenes)
RN  - 0 (DNA Adducts)
RN  - 0 (Pyrimidines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (benz(a)anthracene-3,4-dione)
RN  - 65199-11-3 (benzo(a)pyrene-7,8-dione)
RN  - 789U1901C5 (Copper)
RN  - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
RN  - 9007-49-2 (DNA)
RN  - 91080-16-9 (calf thymus DNA)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.1.- (Alcohol Oxidoreductases)
RN  - EC 1.1.1.- (Aldo-Keto Reductases)
RN  - EC 1.1.1.21 (Aldehyde Reductase)
RN  - G9481N71RO (Deoxyguanosine)
SB  - IM
MH  - 8-Hydroxy-2'-Deoxyguanosine
MH  - Alcohol Oxidoreductases/*chemistry/metabolism
MH  - Aldehyde Reductase
MH  - Aldo-Keto Reductases
MH  - Benz(a)Anthracenes/*chemistry/metabolism
MH  - Benzopyrenes/*chemistry/metabolism
MH  - Copper/chemistry/metabolism
MH  - DNA/chemistry/metabolism
MH  - DNA Adducts/analysis
MH  - Deoxyguanosine/*analogs & derivatives/chemistry/metabolism
MH  - Iron/chemistry/metabolism
MH  - Oxidation-Reduction
MH  - Pyrimidines/chemistry/metabolism
MH  - Reactive Oxygen Species/chemistry/metabolism
PMC - PMC2366214
MID - NIHMS46324
EDAT- 2006/05/16 09:00
MHDA- 2006/07/11 09:00
PMCR- 2008/05/05
CRDT- 2006/05/16 09:00
PHST- 2006/05/16 09:00 [pubmed]
PHST- 2006/07/11 09:00 [medline]
PHST- 2006/05/16 09:00 [entrez]
PHST- 2008/05/05 00:00 [pmc-release]
AID - 10.1021/tx0600245 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2006 May;19(5):719-28. doi: 10.1021/tx0600245.