We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET(A)/ET(B) in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET(A)/ET(B), or with atrasentan, a selective ET(A) receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (13C; 03% in rat chow), a natural xenobiotic which activates the Cyplal promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of 13C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.
- MeSH
- angiotensin II krev metabolismus MeSH
- antagonisté endotelinového receptoru MeSH
- antihypertenziva farmakologie MeSH
- cytochrom P-450 CYP1A1 genetika účinky léků MeSH
- endotelin-1 MeSH
- hypertenze farmakoterapie chemicky indukované MeSH
- indoly škodlivé účinky MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus MeSH
- modely nemocí na zvířatech MeSH
- potkani transgenní MeSH
- pyrrolidiny farmakologie MeSH
- receptory endotelinů MeSH
- renin genetika MeSH
- srdeční komory metabolismus MeSH
- sulfonamidy farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- buněčné linie účinky léků MeSH
- cytochrom P-450 CYP1A1 metabolismus účinky léků MeSH
- dexamethason farmakologie MeSH
- dioxiny farmakologie metabolismus MeSH
- financování organizované MeSH
- glukokortikoidy farmakologie MeSH
- interakce mezi receptory a ligandy účinky léků MeSH
- lidé MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody využití MeSH
- receptory aromatických uhlovodíků účinky léků MeSH
- represorové proteiny účinky léků MeSH
- trofoblasty účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- abstrakty MeSH
3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the (32)P-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential.
- MeSH
- adukty DNA metabolismus MeSH
- benz(a)anthraceny farmakologie toxicita MeSH
- cytochrom P-450 CYP1A1 metabolismus účinky léků MeSH
- cytosol metabolismus účinky léků MeSH
- enzymová indukce MeSH
- financování organizované MeSH
- jaterní mikrozomy metabolismus účinky léků MeSH
- karcinogeny farmakologie toxicita MeSH
- krysa rodu rattus MeSH
- látky znečišťující životní prostředí farmakologie toxicita MeSH
- ledviny metabolismus účinky léků MeSH
- mutageny farmakologie toxicita MeSH
- NAD(P)H dehydrogenasa (chinon) metabolismus účinky léků MeSH
- plíce metabolismus účinky léků MeSH
- potkani Wistar MeSH
- radioizotopy fosforu MeSH
- testy genotoxicity MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- buněčný cyklus MeSH
- cytochrom P-450 CYP1A1 genetika účinky léků MeSH
- cytoskelet účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- hepatocyty MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- mikrotubuly MeSH
- polychlorované dibenzodioxiny farmakologie MeSH
- Check Tag
- krysa rodu rattus MeSH
- MeSH
- antinematodní látky farmakologie MeSH
- cytochrom P-450 CYP1A1 metabolismus účinky léků MeSH
- financování organizované MeSH
- Galliformes metabolismus MeSH
- hepatocyty enzymologie MeSH
- mebendazol analogy a deriváty farmakologie MeSH
- oxidoreduktasy účinky léků MeSH
- systém (enzymů) cytochromů P-450 účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- cytochrom P-450 CYP1A1 účinky léků MeSH
- flavonoidy farmakologie MeSH
- játra enzymologie MeSH
- krysa rodu rattus MeSH
- kur domácí MeSH
- mikrozomy enzymologie MeSH
- modely u zvířat MeSH
- střeva enzymologie MeSH
- systém (enzymů) cytochromů P-450 účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
