Carcinogenesis, Vol. 23, No. 4, 617-625,
April 2002
© 2002 Oxford University Press
CARCINOGENESIS |
Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy
1 Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030,128 40 Prague 2, The Czech Republic,
2 Department of Molecular Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the 32P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N6-yl)aristolactam I, 7-(deoxyguanosin-N2-yl)aristolactam I and 7-(deoxyadenosin-N6-yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin-N2-yl)aristolactam II and 7-(deoxyadenosin-N6-yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Xue, Y. Xiao, H. Zhu, H. Wang, Y. Liu, T. Xie, and J. Ren Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury Nephrol. Dial. Transplant., May 27, 2008; (2008) gfn262v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shibutani, H. Dong, N. Suzuki, S. Ueda, F. Miller, and A. P. Grollman Selective Toxicity of Aristolochic Acids I and II Drug Metab. Dispos., July 1, 2007; 35(7): 1217 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Chan, H.-B. Luo, Y. Zheng, Y.-K. Cheng, and Z. Cai Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats Drug Metab. Dispos., June 1, 2007; 35(6): 866 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dong, N. Suzuki, M. C. Torres, R. R. Bonala, F. Johnson, A. P. Grollman, and S. Shibutani QUANTITATIVE DETERMINATION OF ARISTOLOCHIC ACID-DERIVED DNA ADDUCTS IN RATS USING 32P-POSTLABELING/POLYACRYLAMIDE GEL ELECTROPHORESIS ANALYSIS Drug Metab. Dispos., July 1, 2006; 34(7): 1122 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Arlt, M. Stiborova, C. J. Henderson, M. R. Osborne, C. A. Bieler, E. Frei, V. Martinek, B. Sopko, C. R. Wolf, H. H. Schmeiser, et al. Environmental Pollutant and Potent Mutagen 3-Nitrobenzanthrone Forms DNA Adducts after Reduction by NAD(P)H:Quinone Oxidoreductase and Conjugation by Acetyltransferases and Sulfotransferases in Human Hepatic Cytosols Cancer Res., April 1, 2005; 65(7): 2644 - 2652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stiborova, M. Miksanova, S. Smrcek, C. A. Bieler, A. Breuer, K. A. Klokow, H. H. Schmeiser, and E. Frei Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans Carcinogenesis, May 1, 2004; 25(5): 833 - 840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stiborova, E. Frei, B. Sopko, K. Sopkova, V. Markova, M. Lankova, T. Kumstyrova, M. Wiessler, and H. H. Schmeiser Human cytosolic enzymes involved in the metabolic activation of carcinogenic aristolochic acid: evidence for reductive activation by human NAD(P)H:quinone oxidoreductase Carcinogenesis, October 1, 2003; 24(10): 1695 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stiborova, V. Martinek, H. Rydlova, P. Hodek, and E. Frei Sudan I Is a Potential Carcinogen for Humans: Evidence for Its Metabolic Activation and Detoxication by Human Recombinant Cytochrome P450 1A1 and Liver Microsomes Cancer Res., October 15, 2002; 62(20): 5678 - 5684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Arlt, M. Stiborova, and H. H. Schmeiser Aristolochic acid as a probable human cancer hazard in herbal remedies: a review Mutagenesis, July 1, 2002; 17(4): 265 - 277. [Abstract] [Full Text] [PDF]
|
|