title: Bioactivation versus detoxication of the urothelial carcinogen aristolochic acid I by human cytochrome P450 1A1 and 1A2.
abstract: Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. Individual susceptibility to AA-induced disease likely reflects individual differences in enzymes that metabolize AA. Herein, we evaluated AAI metabolism by human cytochrome P450 (CYP) 1A1 and 1A2 in two CYP1A-humanized mouse lines that carry functional human CYP1A1 and CYP1A2 genes in the absence of the mouse Cyp1a1/1a2 orthologs. Human and mouse hepatic microsomes and human CYPs were also studied. Human CYP1A1 and 1A2 were found to be principally responsible for reductive activation of AAI to form AAI-DNA adducts and for oxidative detoxication to 8-hydroxyaristolochic acid (AAIa), both in the intact mouse and in microsomes. Overall, AAI-DNA adduct levels were higher in CYP1A-humanized mice relative to wild-type mice, indicating that expression of human CYP1A1 and 1A2 in mice leads to higher AAI bioactivation than in mice containing the mouse CYP1A1 and 1A2 orthologs. Furthermore, an exclusive role of human CYP1A1 and 1A2 in AAI oxidation to AAIa was observed in human liver microsomes under the aerobic (i.e., oxidative) conditions. Because CYP1A2 levels in human liver are at least 100-fold greater than those of CYP1A1 and there exists a > 60-fold genetic variation in CYP1A2 levels in human populations, the role of CYP1A2 in AAI metabolism is clinically relevant. The results suggest that, in addition to CYP1A1 and 1A2 expression levels, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic. stiborov@natur.cuni.cz
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.forename: Katerina
authors.initials: K
authors.lastname: Levová
authors.forename: Frantisek
authors.initials: F
authors.lastname: Bárta
authors.forename: Zhanquan
authors.initials: Z
authors.lastname: Shi
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003600:Cytosol / Q000201:enzymology; D018736:DNA Adducts / Q000378:metabolism; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism; D014571:Urologic Neoplasms / Q000139:chemically induced; D019459:Urothelium / Q000187:drug effects
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C000228:aristolochic acid I; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2
references.citation: Cancer Res. 1996 May 1;56(9):2025-8
references.pmid: 8616845
references.citation: Drug Metab Rev. 1997 Feb-May;29(1-2):413-580
references.pmid: 9187528
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12129-34
references.pmid: 17620607
references.citation: Nat Protoc. 2007;2(11):2772-81
references.pmid: 18007613
references.citation: Biochem Biophys Res Commun. 2008 Nov 28;376(4):775-80
references.pmid: 18814841
references.citation: Curr Opin Drug Discov Devel. 2009 Jan;12(1):141-8
references.pmid: 19152223
references.citation: Nat Rev Cancer. 2002 Jan;2(1):38-47
references.pmid: 11902584
references.citation: Int J Cancer. 2002 Oct 10;101(5):500-2
references.pmid: 12216081
references.citation: Int J Cancer. 2011 Jan 1;128(1):21-32
references.pmid: 20232387
references.citation: Lancet. 1993 Feb 13;341(8842):387-91
references.pmid: 8094166
references.citation: Cancer Res. 2004 Nov 15;64(22):8374-80
references.pmid: 15548707
references.citation: Toxicol Sci. 2011 May;121(1):43-56
references.pmid: 21362632
references.citation: Mol Endocrinol. 1989 Sep;3(9):1399-408
references.pmid: 2575218
references.citation: Biochem Biophys Res Commun. 2007 Aug 3;359(3):635-42
references.pmid: 17560947
references.citation: Lancet Oncol. 2009 Jan;10(1):13-4
references.pmid: 19115512
references.citation: Environ Mol Mutagen. 2011 Jul;52(6):448-59
references.pmid: 21370283
references.citation: Neuro Endocrinol Lett. 2008 Oct;29(5):733-7
references.pmid: 18987598
references.citation: Mutat Res. 2008 Jan-Feb;658(1-2):55-67
references.pmid: 17851120
references.citation: Mol Nutr Food Res. 2005 Feb;49(2):101-17
references.pmid: 15617087
references.citation: J Nephrol. 2004 May-Jun;17(3):384-9
references.pmid: 15365958
references.citation: Am J Kidney Dis. 2008 Mar;51(3):471-7
references.pmid: 18295063
references.citation: Chem Res Toxicol. 2005 Sep;18(9):1471-8
references.pmid: 16167840
references.citation: Clin Biochem. 2005 Mar;38(3):223-8
references.pmid: 15708542
references.citation: Cancer Res. 2002 Oct 15;62(20):5678-84
references.pmid: 12384524
references.citation: Mol Carcinog. 1989;2(4):192-8
references.pmid: 2803520
references.citation: Chem Res Toxicol. 2011 Oct 17;24(10):1710-9
references.pmid: 21932800
references.citation: Int J Cancer. 2010 Sep 1;127(5):1021-7
references.pmid: 20039324
references.citation: Cancer Lett. 2005 Apr 8;220(2):145-54
references.pmid: 15766589
references.citation: Drug Metab Dispos. 2010 May;38(5):761-8
references.pmid: 20164109
references.citation: Carcinogenesis. 2003 Oct;24(10):1695-703
references.pmid: 12869422
references.citation: Carcinogenesis. 2007 Nov;28(11):2253-61
references.pmid: 17434925
references.citation: Cancer Lett. 2005 Nov 18;229(2):193-204
references.pmid: 16125300
references.citation: Kidney Int. 2008 Jul;74(2):158-69
references.pmid: 18418355
references.citation: Nat Rev Nephrol. 2010 Nov;6(11):667-78
references.pmid: 20877304
references.citation: Int J Cancer. 2005 Jan 10;113(2):189-97
references.pmid: 15386410
references.citation: Nephrol Dial Transplant. 2008 Oct;23(10):3074-81
references.pmid: 18495746
references.citation: N Engl J Med. 2000 Jun 8;342(23):1686-92
references.pmid: 10841870
references.citation: Am J Physiol Cell Physiol. 2006 Jan;290(1):C37-41
references.pmid: 16338979
references.citation: Chem Res Toxicol. 2001 Aug;14(8):1128-37
references.pmid: 11511187
references.citation: Rapid Commun Mass Spectrom. 2006;20(11):1755-60
references.pmid: 16676316