title: Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy.
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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. Electronic address: stiborov@natur.cuni.cz.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.affiliation: Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.affiliation: Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000737:chemistry / Q000378:metabolism*; D001449:Balkan Nephropathy / Q000378:metabolism* / Q000473:pathology; D001711:Biotransformation; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D012307:Risk Factors
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D019388:Cytochrome P-450 CYP1A2