Linked Life Data

11989648

Source:http://linkedlifedata.com/resource/pubmed/id/11989648

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-5-6
pubmed:abstractText
Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been found to be implicated in an unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN), and associated with the development of urothelial cancer in CHN patients. Understanding, which enzymes are involved in AA activation and/or detoxication is important in the assessment of individual susceptibility of humans to this natural carcinogen. Using the nuclease P1 version of the 32P-postlabeling assay we examined the ability of microsomal NADPH: CYP reductase to activate AA to metabolites forming DNA adducts. Renal and hepatic microsomes, containing NADPH:CYP reductase, generated AA-DNA adduct patterns reproducing those found in renal tissues in patients suffering from a renal fibrosis CHN and urothelial cancer. 7-(Deoxyadenosin-N6-yl)aristolactam I, 7-(deoxyguanosin-N2-yl)aristolactam I and 7-(deoxyadenosin-N6-yl)aristolactam II were identified as AA-DNA adducts formed by AAI. Two AA-DNA adducts, 7-(deoxyguanosin-N2-yl) aristolactam II and 7- (deoxyadenosin-N6-yl) aristolactam II, were generated from AAII. According to the structures of the DNA adducts identified, nitroreduction is the crucial pathway in the metabolic activation of AA. The identity of NADPH: CYP reductase as activating enzyme in microsomes has been proved with different cofactors and an enzyme inhibitor. Alpha-lipoic acid, a selective inhibitor of NADPH: CYP reductase, significantly decreased the amount of the adducts formed by microsomes. Likewise, only a cofactor of the enzyme, NADPH, supported the DNA adduct formation of AAI and AAII, while NADH was ineffective. These results demonstrate an involvement of NADPH: CYP reductase in the activation pathway of AAI and AAII in the microsomal system. Moreover, using the purified enzyme, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The results presented here are the first report demonstrating a reductive activation of natural nitroaromatic compounds, AA, by NADPH: CYP reductase.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0231-5882
pubmed:author
pubmed:issnType
Print
pubmed:volume
20
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
375-92
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11989648-Animals, pubmed-meshheading:11989648-Aristolochic Acids, pubmed-meshheading:11989648-Carcinogens, pubmed-meshheading:11989648-Cattle, pubmed-meshheading:11989648-DNA, pubmed-meshheading:11989648-DNA Adducts, pubmed-meshheading:11989648-Dose-Response Relationship, Drug, pubmed-meshheading:11989648-Drugs, Chinese Herbal, pubmed-meshheading:11989648-Enzyme Activation, pubmed-meshheading:11989648-Kidney, pubmed-meshheading:11989648-Liver, pubmed-meshheading:11989648-Male, pubmed-meshheading:11989648-Microsomes, Liver, pubmed-meshheading:11989648-Models, Chemical, pubmed-meshheading:11989648-NADPH-Ferrihemoprotein Reductase, pubmed-meshheading:11989648-Phenanthrenes, pubmed-meshheading:11989648-Rats, pubmed-meshheading:11989648-Rats, Wistar, pubmed-meshheading:11989648-Time Factors
pubmed:year
2001
pubmed:articleTitle
Carcinogenic and nephrotoxic alkaloids aristolochic acids upon activation by NADPH : cytochrome P450 reductase form adducts found in DNA of patients with Chinese herbs nephropathy.
pubmed:affiliation
Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic. stiborov@natur.cuni.cz
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't