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  • 1
    Keywords: INHIBITOR ; IN-VIVO ; INHIBITION ; LUNG ; LUNG-CANCER ; DNA adducts ; liver ; ENZYMES ; TISSUE ; MICE ; ACTIVATION ; DNA ; kidney ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; AIR-POLLUTION ; CONTAMINANT 3-NITROBENZANTHRONE ; BINDING ; DNA-BINDING ; METABOLIC-ACTIVATION ; ADDUCTS ; rodent ; DT-DIAPHORASE ; RAT-LIVER CYTOSOL ; XANTHINE-OXIDASE ; DNA-ADDUCTS ; V79 CELLS ; ACETYLTRANSFERASE ; ADDUCT ; COFACTOR ; CARCINOGENIC ARISTOLOCHIC ACIDS ; CYTOCHROME-P450 1A1 ; MUTAGEN 3-NITROBENZANTHRONE ; SULFOTRANSFERASES ; DNA ADDUCT ; sulfotransferase
    Abstract: 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and air pollution. We compared the ability of human hepatic cytosolic samples to catalyze DNA adduct formation by 3-NBA. Using the (32)p-postlabeling method, we found that 12/12 hepatic cytosols activated 3-NBA to form multiple DNA adducts similar to those formed in vivo in rodents. By comparing 3-NBA-DNA adduct formation in the presence of cofactors of NAD(P)H:quinone oxidoreductase (NQO1) and xanthine oxidase, most of the reductive activation of 3-NBA in human hepatic cytosols was attributed to NQO1. Inhibition of adduct formation by dicoumarol, an NQO1 inhibitor, supported this finding and was confirmed with human recombinant NQO1. When cofactors of N,O-acetyltransferases (NAT) and sulfotransferases (SUIT) were added to cytosolic samples, 3-NBA-DNA adduct formation increased 10- to 35-fold. Using human recombinant NQO1 and NATs or SULTs, we found that mainly NAT2, followed by SULT1A2, NAT1, and, to a lesser extent, SULT1A1 activate 3-NBA. We also evaluated the role of hepatic NADPH:cytochrome P450 oxidoreductase (POR) in the activation of 3-NBA in vivo by treating hepatic POR-null mice and wild-type littermates i.p. with 0.2 or 2 mg/kg body weight of 3-NBA. No difference in DNA binding was found in any tissue examined (liver, lung, kidney, bladder, and colon) between null and wild-type mice, indicating that 3-NBA is predominantly activated by cytosolic nitroreductases rather than microsomal POR. Collectively, these results show the role of human hepatic NQO1 to reduce 3-NBA to species being further activated by NATs and SULTs
    Type of Publication: Journal article published
    PubMed ID: 15805261
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  • 2
    Keywords: CANCER ; IN-VITRO ; INHIBITOR ; human ; liver ; SITE ; ENZYMES ; SAMPLE ; SAMPLES ; METABOLISM ; TISSUE ; TIME ; ACTIVATION ; DNA ; kidney ; renal ; DNA ADDUCT FORMATION ; metabolic activation ; RAT ; TISSUES ; SUSCEPTIBILITY ; ACID ; RAT-LIVER ; PATTERNS ; ASSAY ; MODULATION ; POLYCYCLIC AROMATIC-HYDROCARBONS ; HUMAN LIVER ; rat liver ; ORIENTATION ; HUMAN-LIVER ; aristolochic acid ; aldehyde ; BALKAN ENDEMIC NEPHROPATHY ; CHINESE HERBS NEPHROPATHY ; DT-DIAPHORASE ; P-32 POSTLABELING ANALYSIS ; QUINONE REDUCTASE ; RAT-LIVER CYTOSOL ; XANTHINE-OXIDASE
    Abstract: 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 P-32-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-N-6-yl)aristolactam I, 7-(deoxyguanosin-N-2-yl)aristolactam I and 7-(deoxyadenosin-N-6-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
    Type of Publication: Journal article published
    PubMed ID: 12869422
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