PMID- 15606153
OWN - NLM
STAT- MEDLINE
DCOM- 20050614
LR  - 20121115
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 17
IP  - 12
DP  - 2004 Dec
TI  - Oxidative DNA damage induced by carcinogenic dinitropyrenes in the presence of 
      P450 reductase.
PG  - 1750-6
AB  - Nitropyrenes are widespread in the environment due to mainly diesel engine 
      emissions. Dinitropyrenes (DNPs), especially 1,8-dinitropyrene (1,8-DNP) and 
      1,6-dinitropyrene (1,6-DNP), are much more potent mutagens than other 
      nitropyrenes. The carcinogenicity of 1,8-DNP and 1,6-DNP is stronger than 
      1,3-dinitropyrene (1,3-DNP). It is considered that adduct formation after 
      metabolic activation plays an important role in the expression of carcinogenicity 
      of nitropyrenes. However, Djuric et al. [(1993) Cancer Lett.] reported that 
      oxidative DNA damage was also found as well as adduct formation in rats treated 
      with 1,6-DNP. We investigated oxidative DNA damage by DNPs in the presence of 
      NAD(P)H-cytochrome P450 reductase using 32P-5'-end-labeled DNA. After P450 
      reductase treatment, DNPs induced Cu(II)-mediated DNA damage in the presence of 
      NAD(P)H. The intensity of DNA damage by 1,8-DNP or 1,6-DNP was stronger than 
      1,3-DNP. We also examined synthetic 1-nitro-8-nitrosopyrene (1,8-NNOP) and 
      1-nitro-6-nitrosopyrene (1,6-NNOP) as one of the metabolites of 1,8-DNP and 
      1,6-DNP, respectively, to find that 1,8-NNOP and 1,6-NNOP induced Cu(II)-mediated 
      DNA damage in the presence of NAD(P)H but untreated DNPs did not. In both cases 
      of P450 reductase-treated DNPs and NNOPs, catalase and a Cu(I) specific chelator 
      attenuated DNA damage, indicating the involvement of H2O2 and Cu(I). Using a 
      Clarke oxygen electrode, oxygen consumption by the reaction of NNOPs with NAD(P)H 
      and Cu(II) was measured to find that NNOP was nonenzymatically reduced by NAD(P)H 
      and that the addition of Cu(II) promoted the redox cycle. Therefore, these 
      results suggest that DNPs are enzymatically reduced to NNOPs via nitro radical 
      anion and that NNOPs are further reduced nonenzymatically by NAD(P)H. 
      Subsequently, autoxidation of nitro radical anion and the reduced form of NNOP 
      occurs, resulting in O2- generation and DNA damage. We conclude that oxidative 
      DNA damage in addition to DNA adduct formation may play important roles in the 
      carcinogenesis of DNPs via their metabolites.
FAU - Murata, Mariko
AU  - Murata M
AD  - Department of Environmental and Molecular Medicine, Mie University School of 
      Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan.
FAU - Ohnishi, Shiho
AU  - Ohnishi S
FAU - Seike, Kazuharu
AU  - Seike K
FAU - Fukuhara, Kiyoshi
AU  - Fukuhara K
FAU - Miyata, Naoki
AU  - Miyata N
FAU - Kawanishi, Shosuke
AU  - Kawanishi S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Carcinogens)
RN  - 0 (Free Radical Scavengers)
RN  - 0 (Phenanthrolines)
RN  - 0 (Pyrenes)
RN  - 51U7E9MW6I (1,8-dinitropyrene)
RN  - 9007-49-2 (DNA)
RN  - 9THP2V94FX (bathocuproine)
RN  - EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase)
SB  - IM
MH  - Animals
MH  - Carcinogens/toxicity
MH  - Cattle
MH  - DNA/metabolism
MH  - *DNA Damage
MH  - Free Radical Scavengers/metabolism
MH  - Humans
MH  - NADPH-Ferrihemoprotein Reductase/*pharmacology
MH  - *Oxidative Stress
MH  - Phenanthrolines/chemistry
MH  - Pyrenes/*toxicity
MH  - Rats
EDAT- 2004/12/21 09:00
MHDA- 2005/06/15 09:00
CRDT- 2004/12/21 09:00
PHST- 2004/12/21 09:00 [pubmed]
PHST- 2005/06/15 09:00 [medline]
PHST- 2004/12/21 09:00 [entrez]
AID - 10.1021/tx0497550 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2004 Dec;17(12):1750-6. doi: 10.1021/tx0497550.