Monomethylated benz[ a]anthracenes (MeBaAs) are an important group of methylated derivatives of polycyclic aromatic hydrocarbons (PAHs). Although the methyl substitution reportedly affects their mutagenicity and tumor-initiating activity, little is known about the impact of methylation on the effects associated with activation of the aryl hydrocarbon receptor (AhR)-dependent gene expression and/or toxic events associated with tumor promotion. In the present study, we studied the effects of a series of MeBaAs on the above-mentioned end points in rat liver cell lines and compared them with the effects of benz[ a]anthracene (BaA) and the potent carcinogen 7,12-dimethylbenz[ a]anthracene (DMBA). Methyl substitution enhanced the AhR-mediated activity of BaA derivatives determined in a reporter gene assay, as the induction equivalency factors (IEFs) of all MeBaAs were higher than that of BaA. IEFs of 6-MeBaA and 9-MeBaA, two of the most potent MeBaAs, were more than two orders of magnitude higher than the IEF of BaA. Correspondingly, all MeBaAs induced higher levels of cytochrome P450 1A1 mRNA. Both BaA and MeBaAs had similar effects on the expression of cytochrome P450 1B1 or aldo-keto reductase 1C9 in rat liver epithelial WB-F344 cells. In contrast to genotoxic DMBA, MeBaAs induced low DNA adduct formation. Only 10-MeBaA induced apoptosis and accumulation of phosphorylated p53, which could be associated with the induction of oxidative stress, similar to DMBA. With the exception of 10-MeBaA, all MeBaAs induced cell proliferation in contact-inhibited WB-F344 cells, which corresponded with their ability to activate AhR. 1-, 2-, 8-, 10-, 11-, and 12-MeBaA inhibited gap junctional intercellular communication (GJIC) in WB-F344 cells. This mode of action, like disruption of cell proliferation control, might contribute to tumor promotion. Taken together, these data showed that the methyl substitution significantly influences those effects of MeBaAs associated with AhR activation or GJIC inhibition.

• MeSH
• 9,10-dimethyl-1,2-benzanthracen imunologie   metabolismus   toxicita   MeSH
• adukty DNA analýza   metabolismus   MeSH
• apoptóza účinky léků   MeSH
• benz(a)anthraceny chemie   metabolismus   toxicita   MeSH
• DNA metabolismus   účinky léků   MeSH
• enzymová indukce MeSH
• financování organizované MeSH
• hepatocelulární karcinom MeSH
• hepatocyty metabolismus   patologie   účinky léků   MeSH
• kmenové buňky metabolismus   patologie   účinky léků   MeSH
• krysa rodu rattus MeSH
• messenger RNA metabolismus   MeSH
• metylace MeSH
• mezerový spoj účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory jater MeSH
• potkani inbrední F344 MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• reportérové geny účinky léků   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

Alkylated polycyclic aromatic hydrocarbons (PAHs) are important environmental pollutants. In the present study, we determined levels of monomethylated naphthalenes (MeNap), phenanthrenes (MePhe), and anthracenes (MeAnt) in Czech river sediments. The levels of MePhe generally were lower than the concentrations of phenanthrene. In contrast, both MeNap and MeAnt were found at levels higher than their respective parent compounds in the majority of sampling sites. We then investigated their aryl hydrocarbon receptor (AhR)-mediated activity, accumulation of phosphorylated p53 protein, induction of expression of cytochrome P450 1A1 (CYP1A1), inhibition of gap junctional intercellular communication (GJIC), and effects on cell proliferation in rat liver cell models to evaluate the relative importance of these toxicity mechanisms of low-molecular-weight methylated PAHs. Methylated phenanthrene and anthracene compounds were weak inducers of AhR-mediated activity as determined both in a reporter gene assay system and by detection of the endogenous gene (Cyp1a1) induction. 2-Methylphenanthrene was the most potent AhR ligand. Contribution of MeAnt and MePhe to overall AhR-inducing potencies should be taken into account in PAH-contaminated environments. Nevertheless, their effects on AhR were not sufficient to modulate cell proliferation in a normal rat liver progenitor cell model system. These PAHs only had a marginal effect on p53 phosphorylation at high doses of 1-, 3-, and 9-MePhe as well as 1 MeAnt. On the other hand, both 2- and 9-MeAnt as well as all the MePhe under study were efficient inhibitors of GJIC, suggesting that these compounds might act as tumor promoters. In summary, inhibition of GJIC and partial activation of AhR seem to be the most prominent toxic effects of the methylated PAHs in the present study.

• MeSH
• anthraceny toxicita   MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• fenantreny toxicita   MeSH
• financování organizované MeSH
• geologické sedimenty chemie   MeSH
• játra cytologie   patologie   MeSH
• karcinogeny toxicita   MeSH
• krysa rodu rattus MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• metylace MeSH
• mezerový spoj metabolismus   účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• naftaleny toxicita   MeSH
• proliferace buněk účinky léků   MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• regulace genové exprese fyziologie   účinky léků   MeSH
• řeky MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Geografické názvy
• Česká republika MeSH

• Publikační typ
• abstrakt z konference MeSH

Semisynthetic derivatives of daunomycinone with 7,9-isopropylacetal, 7-O-methyl, 7-O-(4-penten-2-yl), and 7-O-(2-hydroxyethyl) substituents were converted by Streptomyces peucetius var. caesius (an adriamycin-blocked mutant) into 7-deoxy-13-dihydrodaunomycinone, while daunomycinone was transformed into 13-dihydrodaunomycinone (predominantly) and 7-deoxy-13-dihydrodaunomycinone. S. coeruleorubidus mutants 24-74 (accumulating aclavinone derivatives instead of daunomycin and related compounds) and 96-85 (producing no anthracycline substances), and S. aureofaciens B-96 (a tetracycline-blocked mutant) transformed the above substrates into the corresponding 13-dihydro derivatives, with the exception of 7,9-isopropylacetal daunomycinone which remained intact. 7-O-Propyn-1-yl daunomycinone was not transformed by any of the strains used under the conditions.

• MeSH
• naftaceny metabolismus   MeSH
• Streptomycetaceae metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• anthraceny analýza   MeSH
• benzopyreny analýza   MeSH
• biotest MeSH
• karcinogeny analýza   MeSH
• methylcholanthren analýza   MeSH
• riboflavin analýza   MeSH
• vodík metabolismus   MeSH

• MeSH
• fenotyp MeSH
• krysa rodu rattus MeSH
• methylnitrosomočovina MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH

• MeSH
• anthraceny škodlivé účinky   terapeutické užití   MeSH
• antiflogistika nesteroidní škodlivé účinky   terapeutické užití   MeSH
• hodnocení léčiv * metody   MeSH
• indany kontraindikace   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• trimetazidin škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Východiská: Vysoké hladiny prostaglandínov zistené v mnohých neoplastických tkanivách, hlavne u rakoviny hrubého čreva a prsníka, poukazujú na úlohu cyklooxygenázy v procese karcinogenézy. Materiál a metódy: Cieľom tejto štúdie bolo analyzovať chemopreventívny potenciál samostatne aplikovaného nesteroidného antiflogistika indometacínu a jeho kombinácie s pineálnym hormónom melatonínom v mamárnej karcinogenéze samíc potkanov indukovanej pomocou N-metyl-N-nitrozourey. Indometacín bol podávaný 3-krát a melatonín 4-krát v týždni, obe látky v koncentrácii 20 ?g/ml pitnej vody. Chemoprevencia začala približne 2 týždne pred aplikáciou karcinogénu a trvala do ukončenia experimentu ďalších 25 týždňov. Výsledky: Indometacín aplikovaný samostatne, ale aj v kombinácii s melatonínom stimuloval rast mamárnych tumorov, čo sa prejavilo signifikantným nárastom priemerného objemu nádorov o 126 %, resp. 104 % voči kontrolnej skupine. Samostatne podaný indometacín zvýšil incidenciu nádorov o 21,5 % (rovnako aj v kombinácii s melatonínom) a skrátil latenciu nádorov o 17 dní voči kontrole. Samotný melatonín znížil signifikantne objem nádorov porovnaním s kontrolnými zvieratami. Obe látky boli zvieratami počas dlhodobej aplikácie dobre tolerované. Záver: Indometacín, prevažný inhibítor cyklooxygenázy-1, prejavil signifikantné neoplastické účinky v prevencii N-metyl-N-nitrozoureou indukovanej mamárnej karcinogenézy u potkanov. Toto zistenie je v ostrom protiklade s našim predchádzajúcim experimentom, v ktorom sme mamárnu karcinogenézu u potkanov indukovali 7,12-dimetylbenzantracénom, pričom indometacín v tomto prípade preukázal veľmi výrazné chemopreventívne účinky.

Background: High levels of prostaglandins found in many neoplastic tissues, especially in colon cancer and breast cancer, suggest a role of cyclooxygenase in the process of carcinogenesis. Material and methods: The aim of this study was to analyse the chemopreventive potential of non-steroidal inflammatory drug indomethacin and its combination with pineal hormone melatonin in rat mammary carcinogenesis induced by N-methyl-N-nitrosourea. Indomethacin was administered 3 times a week and melatonin 4 times a week, both substances in a concentration of 20 ?g/ml of drinking water. Chemoprevention began approximately 2 weeks before carcinogen administration and lasted until the end of the experiment 25 weeks later. Results: Indomethacin administered alone and in combination with melatonin stimulated the growth of mammary tumors. We found a significant increase in the average tumor volume caused by indomethacin alone by 126%, and in combination with melatonin by 104% compared to the control group. Indomethacin administered alone increased the incidence of tumors by 21.5% (also in combination with melatonin) and reduced the tumor latency by 17 days compared to controls. Melatonin alone significantly reduced tumor volume in comparison with control animals. During the long-term administration, both substances were well tolerated by animals. Conclusion: Indomethacin, a predominant cyclooxygenase inhibitor-1, showed significant neoplastic effects in the prevention of N-methyl-N-nitrosourea induced rat mammary carcinogenesis. This finding is in strong contrast to our previous experiment, where indomethacin in 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis revealed marked antineoplastic effects. Key words: rats – mammary carcinogenesis – chemoprevention – indomethacin – melatonin Submitted: 23. 2. 2012 Accepted: 30. 4. 2012

• MeSH
• antikarcinogenní látky terapeutické užití   MeSH
• chemoprofylaxe MeSH
• experimentální nádory mléčných žláz * chemicky indukované   prevence a kontrola   MeSH
• financování organizované MeSH
• indomethacin * terapeutické užití   MeSH
• melatonin terapeutické užití   MeSH
• methylnitrosomočovina * MeSH
• potkani Sprague-Dawley * MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví * MeSH
• zvířata MeSH

• MeSH
• anthraceny farmakologie   MeSH
• antidepresiva farmakologie   MeSH
• fysostigmin antagonisté a inhibitory   MeSH
• králíci MeSH
• krysa rodu rattus MeSH
• myši MeSH
• nikotin antagonisté a inhibitory   MeSH
• propylaminy farmakologie   MeSH
• reserpin antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH