Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy.

2.50
Hdl Handle:
http://hdl.handle.net/10146/38101
Title:
Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy.
Authors:
Stiborova, Marie; Frei, Eva; Arlt, Volker M.; Schmeiser, Heinz H.
Abstract:
Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, is associated with tumor development in patients suffering from Chinese herbs nephropathy (now termed aristolochic acid nephropathy, AAN) and may also be a cause for the development of a similar type of nephropathy, the Balkan endemic nephropathy (BEN). Major DNA adducts [7-(deoxyadenosin-N6-yl)-aristolactam and 7-(deoxyguanosin-N2-yl)aristolactam] formed from AA after reductive metabolic activation were found in renal tissues of patients with both diseases. Understanding which human enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual's susceptibility to this plant carcinogen. This paper reviews major hepatic and renal enzymes responsible for AA-DNA adduct formation in humans. Phase I biotransformation enzymes play a crucial role in the metabolic activation of AA to species forming DNA adducts, while a role of phase II enzymes in this process is questionable. Most of the activation of AA in human hepatic microsomes is mediated by cytochrome P450 (CYP) 1A2 and, to a lower extent, by CYP1A1; NADPH:CYP reductase plays a minor role. In human renal microsomes NADPH:CYP reductase is more effective in AA activation. Prostaglandin H synthase (cyclooxygenase, COX) is another enzyme activating AA in human renal microsomes. Among the cytosolic reductases, NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient in the activation of AA in human liver and kidney. Studies with purified enzymes confirmed the importance of CYPs, NADPH:CYP reductase, COX and NQO1 in the AA activation. The orientation of AA in the active sites of human CYP1A1, -1A2 and NQO1 was predicted from molecular modeling and explains the strong reductive potential of these enzymes for AA detected experimentally. We hypothesized that inter-individual variations in expressions and activities of enzymes activating AA may be one of the causes responsible for the different susceptibilities to this carcinogen reflected in the development of AA-induced nephropathies and associated urothelial cancer.
Citation:
Mutat. Res. 658 (1-2):55-67
Journal:
Mutation Research
Issue Date:
24-Sep-2008
URI:
http://hdl.handle.net/10146/38101
DOI:
10.1016/j.mrrev.2007.07.003
PubMed ID:
17851120
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2G-4PC3VWJ-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=1843694&md5=af86f623ad192a58acc27c90ac69d2ef
Type:
Article
Language:
en
ISSN:
0027-5107
Sponsors:
The work is supported by the Grant Agency of the Czech Republic (grant 303/05/2195), the Ministry of Education of the Czech Republic (grant MSM0021620808), German Cancer Research Center and the Association for International Cancer Research (AICR). Volker M. Arlt is a member of the ECNIS (European Environmental Cancer Risk, Nutrition and Individual Susceptibility), network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorStiborova, Marie-
dc.contributor.authorFrei, Eva-
dc.contributor.authorArlt, Volker M.-
dc.contributor.authorSchmeiser, Heinz H.-
dc.date.accessioned2008-09-24T10:45:35Z-
dc.date.available2008-09-24T10:45:35Z-
dc.date.issued2008-09-24T10:45:35Z-
dc.identifier.citationMutat. Res. 658 (1-2):55-67en
dc.identifier.issn0027-5107-
dc.identifier.pmid17851120-
dc.identifier.doi10.1016/j.mrrev.2007.07.003-
dc.identifier.urihttp://hdl.handle.net/10146/38101-
dc.description.abstractAristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, is associated with tumor development in patients suffering from Chinese herbs nephropathy (now termed aristolochic acid nephropathy, AAN) and may also be a cause for the development of a similar type of nephropathy, the Balkan endemic nephropathy (BEN). Major DNA adducts [7-(deoxyadenosin-N6-yl)-aristolactam and 7-(deoxyguanosin-N2-yl)aristolactam] formed from AA after reductive metabolic activation were found in renal tissues of patients with both diseases. Understanding which human enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual's susceptibility to this plant carcinogen. This paper reviews major hepatic and renal enzymes responsible for AA-DNA adduct formation in humans. Phase I biotransformation enzymes play a crucial role in the metabolic activation of AA to species forming DNA adducts, while a role of phase II enzymes in this process is questionable. Most of the activation of AA in human hepatic microsomes is mediated by cytochrome P450 (CYP) 1A2 and, to a lower extent, by CYP1A1; NADPH:CYP reductase plays a minor role. In human renal microsomes NADPH:CYP reductase is more effective in AA activation. Prostaglandin H synthase (cyclooxygenase, COX) is another enzyme activating AA in human renal microsomes. Among the cytosolic reductases, NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient in the activation of AA in human liver and kidney. Studies with purified enzymes confirmed the importance of CYPs, NADPH:CYP reductase, COX and NQO1 in the AA activation. The orientation of AA in the active sites of human CYP1A1, -1A2 and NQO1 was predicted from molecular modeling and explains the strong reductive potential of these enzymes for AA detected experimentally. We hypothesized that inter-individual variations in expressions and activities of enzymes activating AA may be one of the causes responsible for the different susceptibilities to this carcinogen reflected in the development of AA-induced nephropathies and associated urothelial cancer.en
dc.description.sponsorshipThe work is supported by the Grant Agency of the Czech Republic (grant 303/05/2195), the Ministry of Education of the Czech Republic (grant MSM0021620808), German Cancer Research Center and the Association for International Cancer Research (AICR). Volker M. Arlt is a member of the ECNIS (European Environmental Cancer Risk, Nutrition and Individual Susceptibility), network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2G-4PC3VWJ-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=1843694&md5=af86f623ad192a58acc27c90ac69d2efen
dc.subjectAristolochic aciden
dc.subjectAristolochic acid nephropathyen
dc.subjectBalkan endemic nephropathyen
dc.subjectReductive activationen
dc.subjectDNA adductsen
dc.subject.meshAnimals-
dc.subject.meshAristolochic Acids-
dc.subject.meshBalkan Nephropathy-
dc.subject.meshBiotransformation-
dc.subject.meshCarcinogens-
dc.subject.meshCytochrome P-450 CYP1A2-
dc.subject.meshHumans-
dc.subject.meshModels, Chemical-
dc.subject.meshMolecular Structure-
dc.subject.meshRisk Factors-
dc.titleMetabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy.en
dc.typeArticleen
dc.identifier.journalMutation Researchen
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