Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy.
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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.
CitationMutat. Res. 658 (1-2):55-67
SponsorsThe 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).
- Carcinogenic and nephrotoxic alkaloids aristolochic acids upon activation by NADPH : cytochrome P450 reductase form adducts found in DNA of patients with Chinese herbs nephropathy.
- Authors: Stiborová M, Hájek M, Frei E, Schmeiser HH
- Issue date: 2001 Dec
- Human cytosolic enzymes involved in the metabolic activation of carcinogenic aristolochic acid: evidence for reductive activation by human NAD(P)H:quinone oxidoreductase.
- Authors: Stiborová M, Frei E, Sopko B, Sopková K, Marková V, Lanková M, Kumstýrová T, Wiessler M, Schmeiser HH
- Issue date: 2003 Oct
- The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen.
- Authors: Stiborová M, Sopko B, Hodek P, Frei E, Schmeiser HH, Hudecek J
- Issue date: 2005 Nov 18
- The role of biotransformation enzymes in the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions and difficult answers.
- Authors: Stiborova M, Frei E, Arlt VM, Schmeiser HH
- Issue date: 2009 Mar
- Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid-DNA adducts found in patients with urothelial cancer.
- Authors: Stiborová M, Frei E, Hodek P, Wiessler M, Schmeiser HH
- Issue date: 2005 Jan 10