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Chem Biol Interact ; 180(1): 1-9, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19428340


Increasing attention is being paid to the possibility of applying chemopreventive agents for the protection of individuals from cancer risk. The beneficial potential of chemoprotective compounds is usually well documented by extensive experimental data. To assure the desired effect, these compounds are frequently concentrated to produce dietary supplements for human use. The additive and synergistic effects of other food constituents are, however, frequently ignored. Even natural chemopreventive compounds have to be considered as xenobiotics. Thus, as much attention has to be paid to their testing prior to their wide application as is usual in drug development for human treatment. Unfortunately, much of the research in this area is solely based on simplified in vitro systems that cannot take into account the complexity of biotransformation processes, e.g. chemopreventive compound-drug interaction, effect on metabolism of endogenic compounds. Hence, the predicted chemopreventive potential is not attained in respect of cancer prevention; moreover, the administration of high doses of chemopreventive compounds might be even detrimental for the human health.

Anticarcinógenos , Neoplasias/prevención & control , Anticarcinógenos/uso terapéutico , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Factores de Riesgo , Xenobióticos/metabolismo , Xenobióticos/uso terapéutico
Gen Physiol Biophys ; 20(4): 375-92, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11989648


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.

Ácidos Aristolóquicos , Carcinógenos , Aductos de ADN , ADN/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Activación Enzimática , NADPH-Ferrihemoproteína Reductasa/metabolismo , Fenantrenos , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Riñón/patología , Hígado/patología , Masculino , Microsomas Hepáticos/metabolismo , Modelos Químicos , Ratas , Ratas Wistar , Factores de Tiempo
Exp Toxicol Pathol ; 51(4-5): 421-7, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10445409


Aristolochic acid (AA) a naturally occuring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). We identified AA-specific DNA adducts in kidneys and in a ureter obtained from CHN patients after renal transplantation. AA is a plant extract of aristolochia species containing AA I as the major component. Aristolactams are the principal detoxication metabolites of AA, which were detected in urine and faeces from animals and humans. They are activated by cytochrome P450 (P450) and peroxidase to form DNA adducts. Using the 32P-postlabelling assay we investigated the formation of DNA adducts by aristolactam I in these two activation systems. A combination of two independent chromatographic systems (ion-exchange chromatography TLC and reversed-phase HPLC) with reference compounds was used for the identification of adducts. Aristolactam I activated by peroxidase led to the formation of several adducts. Two major adducts were identical to adducts previously observed in vivo. 7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI) were formed in DNA during the peroxidase-mediated one-electron oxidation of aristolactam I. Aristolactam I activated by P450 led to one major adduct and four minor ones. Beside the principal AA-DNA adducts identified recently in the ureter of one patient with CHN, an additional minor adduct was detected, which was found to have indistinguishable chromatographic properties on TLC and HPLC from the major adduct formed from aristolactam I by P450 activation. Thus, this minor AA-adduct might be evolved from the AAI detoxication metabolite (aristolactam I) by P450 activation. These results indicate a potential carcinogenic effect of aristolactam I in humans.

Ácidos Aristolóquicos , Aductos de ADN/metabolismo , Dioxoles/metabolismo , Medicamentos Herbarios Chinos/efectos adversos , Indoles/metabolismo , Enfermedades Renales/inducido químicamente , Fenantrenos/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/metabolismo , ADN/metabolismo , Aductos de ADN/análisis , Dioxoles/análisis , Fibrosis , Peroxidasa de Rábano Silvestre/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Indoles/análisis , Masculino , Ratas , Ratas Sprague-Dawley , Uréter/química
Carcinogenesis ; 18(5): 1063-7, 1997 May.
Artículo en Inglés | MEDLINE | ID: mdl-9163697


Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.

Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/genética , Fenantrenos/química , Adulto , Animales , Aductos de ADN/metabolismo , Femenino , Humanos , Enfermedades Renales/inducido químicamente , Masculino , Persona de Mediana Edad , Ratas , Ratas Wistar , Factores de Tiempo