期刊
CANCER LETTERS
卷 229, 期 2, 页码 193-204出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2005.06.038
关键词
aristolochic acid; carcinogen; urothelial cancer; cytochromes P450 1A1 and 1A2; reductive activation; DNA adduct; computer modeling; docking
类别
Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been associated with the development of urothelial cancer in humans. Using the P-32-postlabeling assay we showed that AAI is activated by human recombinant cytochrome P450 (CYP) 1A1, CYPIA2 and NADPH:CYP reductase to species generating DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N-6-yl)aristolactam I, 7-(deoxyguanosin-N-2-yl) aristolactam I and 7-(deoxyadenosin-N-6-yl)aristolactam II were identified as AA-DNA adducts formed from AAI by the enzymes. The formation of these AA-derived DNA adducts indicates that all the human enzymes reduce the nitro group of AAI to the putative reactive cyclic nitrenium ion responsible for adduct formation. The concentrations of AAI required for its half-maximum DNA binding were 38,65 and 126 mu M AAI for reductive activation by human CYP1A2, CYP1A1 and NADPH:CYP reductase, respectively. CYP1A1 and 1A2 homology modeling followed by docking of AAI to the CYP1A1 and 1A2 active centers was utilized to explain the potential of these enzymes to reduce AAI. Models of human CYP1A1 and 1A2 were constructed on the basis of the crystallographic structure of truncated mammalian CYP enzymes, CYP2B4, 2C5, 2C8, 2C9 and 3A4. The in silico docking of AAI to the active sites of CYP1A1I and 1A2 indicates that AAI binds as an axial ligand of the heme iron and that the nitro group of AAI is in close vicinity to the heme iron of CYPIA2 in an orientation allowing the efficient reduction of this group observed experimentally. The orientation of AAI in the active centre of CYP1A1 however causes an interaction of the heme iron with both the nitro- and the carboxylic groups of AAI. This observation explains the lower reductive potential of CYP1A1 for AAI than CYP1A2, detected experimentally. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
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