geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

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


, : Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy. Mutation Research 658(1-2): 55-67

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-N-6-yl)-aristolactam and 7-(deoxyguanosin-N-2-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 (NQO I) 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.

US$19.90

PMID: 17851120

DOI: 10.1016/j.mrrev.2007.07.003


Other references

Willard, J.E., 1973: Trapped free radicals and electrons in organic glasses. Free radicals, hydrogen atoms, and electrons produced in rigid organic glasses at sufficiently low temperatures have lifetimes of minutes to years. They can be studied by their electron spin resonance spectra and, in the case of electrons, by thei...

Davidson, B.L.; Lee, B., 2016: Gene therapy grows up (and moves out of the house). Human Molecular Genetics 25(R1): R1-R1

Ivashkin, V.M.; Leikina, E.S.; Shikhobalova, N.P., 1978: The nematodes of animals which also parasitize man. The nematodes of animals which may parasitize man are divided into 2 groups: those which become mature in man, developing similarly and with similar pathogenesis in both man and animals and those nematodes which do not mature in man but undergo di...

Sauerlander, R.; Eckert, J., 1974: Die Achatschnecke (Achatina fulica) als experimenteller Zwischenwirt fur Angiostrongylus vasorum (Nematoda). Zeitschrift Parasitenk, 441: 59-72

Rheinheimer, J., 1990: Misophricoides callitriphilus gen. et sp. n., eine neue Russelkafergattung und -art aus Australien. (Insecta, Coleoptera, Curculionidae: Erirhininae). Reichenbachia, 281: 43-45

Braby, L.A.; Ellett, W.H., 1972: Ionization in solid- and grid-walled detectors. Radiation Research 51(3): 569-580

Krejcí, L.; Brettschneider, I.; Praus, R., 1973: Use of hydrophilic gel contact lenses in the treatment of ocular burns due to acids and alkalies. Ceskoslovenska Oftalmologie 29(1): 32-38

Kryukova, N.A., 1966: Pyridoxine metabolism in neurotic patients regularly receiving thiamine. A lengthy parenteral administration of thiamine in a dose of 50 mg impairs the pyridoxine metabolism with ensuing deficiency. In an attempt to attenuate the negative effect of thiamine the latter was introduced together with pyrdoxine. With parent...

Curry, J.M.rris, C.; Walker-Simmons, M., 1991: Sequence analysis of a cDNA ecoding a group 3 LEA and mRNA inducible by ABA or dehydration stress in wheat. A cDNA clone (pMA2005) of a Group 3 LEA (late embryogenesis abundant) protein has been sequenced from wheat. The wheat cDNA clone codes for a protein with ten tandem repeats of an 11 amino acid sequence and has homology to other Group 3 LEAs repor...

Willemot, J., 1964: The Psyche And Rhinoplasty. Acta Oto-Rhino-Laryngologica Belgica 18: 496-503