Human cytosolic enzymes involved in the metabolic activation of carcinogenic aristolochic acid: evidence for reductive activation by human NAD(P)H:quinone oxidoreductase

Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been associated with the development of urothelial cancer in humans. Understanding which human enzymes are involved in AA metabolism is important in the assessment of an individual's susceptibility to this carcinogen....

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Published in:Carcinogenesis (New York) 2003-10, Vol.24 (10), p.1695-1703
Main Authors: Stiborová, Marie, Frei, Eva, Sopko, Bruno, Sopková, Klára, Marková, Vladimíra, Laňková, Martina, Kumstýřová, Tereza, Wiessler, Manfred, Schmeiser, Heinz H.
Format: Article
Language:English
Subjects:
3-dioxolo-5-carboxylic acid
4-d)-1
6-nitro-phenanthro-
7-(deoxyadenosin-N6-yl)aristolactam I
7-(deoxyadenosin-N6-yl)aristolactam II
7-(deoxyguanosin-N2-yl) aristolactam I
7-(deoxyguanosin-N2-yl) aristolactam II
8-methoxy-6-nitro-phenanthro-
AAI
AAII
AAN
Aldehyde Oxidase - metabolism
Animals
aristolochic acid
aristolochic acid nephropathy
Aristolochic Acids - chemistry
Aristolochic Acids - metabolism
Aristolochic Acids - pharmacokinetics
Biological and medical sciences
Biotransformation
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - chemistry
Carcinogens - metabolism
Carcinogens - pharmacokinetics
Chemical agents
Chromatography, High Pressure Liquid
Cytosol - enzymology
dA–AAI
dA–AAII
dG–AAI
dG–AAII
DNA Adducts - analysis
Enzyme Inhibitors - metabolism
Humans
Kidney - enzymology
Liver - enzymology
Male
Medical sciences
Models, Molecular
NAD(P)H Dehydrogenase (Quinone) - analysis
NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors
NAD(P)H Dehydrogenase (Quinone) - metabolism
NAD(P)H:quinone oxidoreductase
NQO1
polyethylenimine
Rats
Rats, Wistar
Tumors
xanthine oxidase
Xanthine Oxidase - analysis
Xanthine Oxidase - antagonists & inhibitors
Xanthine Oxidase - metabolism
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Summary:Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been associated with the development of urothelial cancer in humans. Understanding which human enzymes are involved in AA metabolism is important in the assessment of an individual's susceptibility to this carcinogen. Using the 32P-postlabeling assay we examined the ability of enzymes of cytosolic samples from 10 different human livers and from one human kidney to activate the major component of the plant extract AA, 8-methoxy- 6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI), to metabolites forming adducts in DNA. Cytosolic fractions of both organs generated AAI–DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N6-yl)aristolactam I, 7-(deoxyguanosin-N2-yl)aristolactam I and 7-(deoxyadenosin-N6-yl)aristolactam II, indicating a possible demethoxylation reaction of AAI, were identified as AA–DNA adducts formed from AAI by all human hepatic and renal cytosols. To define the role of human cytosolic reductases in the activation of AAI, we investigated the modulation of AAI–DNA adduct formation by cofactors or selective inhibitors of the NAD(P)H:quinone oxidoreductase (NQO1), xanthine oxidase (XO) and aldehyde oxidase. We also determined whether the activities of NQO1 and XO in different human hepatic cytosolic samples correlated with the levels of AAI–DNA adducts formed by the same cytosolic samples. Based on these studies, we attribute most of the activation of AA in human cytosols to NQO1, although a role of cytosolic XO cannot be ruled out. With purified NQO1 from rat liver and kidney and XO from buttermilk, the major role of NQO1 in the formation of AAI–DNA adducts was confirmed. The orientation of AAI in the active site of human NQO1 was predicted from molecular modeling based on published X-ray structures. The results demonstrate for the first time the potential of human NQO1 to activate AAI by nitroreduction.
ISSN:0143-3334
1460-2180
1460-2180
DOI:10.1093/carcin/bgg119