- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
OBJECTIVES: The aim of this study was to investigate a role of cytochrome P450 (CYP) and peroxidase in ellipticine oxidative activation in two mouse strains differing in expression of NADPH:CYP reductase (POR) [the HRN (Hepatic Cytochrome P450 Reductase Null) mice, in which POR is deleted in hepatocytes and its wild-type (WT) counterpart], and in levels of CYP1A1/2 and cytochrome b5 that were modulated by treatment of these mouse models with a CYP1A inducer, benzo[a]pyrene (BaP). METHODS: Ellipticine-DNA adducts were detected by 32P-postlabeling. HPLC was employed for the separation and characterization of ellipticine metabolites. RESULTS: Hepatic microsomes of HRN and WT mice activate ellipticine to form ellipticine-derived DNA adducts. A 2.2- and 10.4-fold increase in amounts of ellipticine-derived DNA adducts formed by liver microsomes was caused by exposure of HRN and WT mice to BaP, respectively. The results found and utilization of NADPH and arachidonic acid, cofactors of CYP- and cyclooxygenase (COX)-dependent enzyme systems, respectively, as well as inhibitors of CYP1A1/2 and 3A, demonstrate that the CYP1A and 3A enzymes play a major role in ellipticine activation in liver microsomes. In addition, the COX enzyme is important in ellipticine activation in liver of HRN mice. CONCLUSION: The CYP1A and 3A enzymes activate ellipticine mainly in liver of WT mice, whereas peroxidase COX plays this role in liver of HRN mice. Treatment of mice with BaP increases an impact of CYP1A on ellipticine activation. A pattern of expression levels of these enzymes plays a crucial role in their impact on this process.
- MeSH
- antitumorózní látky farmakokinetika MeSH
- benzopyren farmakologie MeSH
- biotransformace účinky léků MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochrom P-450 CYP1A2 metabolismus MeSH
- elipticiny farmakokinetika MeSH
- jaterní mikrozomy účinky léků metabolismus MeSH
- lékové interakce MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- preklinické hodnocení léčiv MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: Cytochrome P450 (CYP) 1A1 is the most important enzyme in both activation and detoxification of carcinogenic benzo[a]pyrene (BaP), in combination with microsomal epoxide hydrolase (mEH). To evaluate metabolism of BaP in human, identification of a suitable animal model that mimics the metabolic fate of BaP in human is of great importance. The aim of this work was to compare BaP oxidation by human CYP1A1 and CYP1A1 of one animal model, rat. Investigation of the effect of cytochrome b5 on BaP oxidation by CYP1A1 was another target of this study. METHODS: High performance liquid chromatography (HPLC) was employed for separation of BaP metabolites formed by enzymatic systems. Their structures were identified by mass- and NMR-spectrometry. RESULTS: Human hepatic microsomes oxidized BaP to BaP-9,10-dihydrodiol, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione and BaP-3-ol. The same metabolites were generated by rat liver microsomes, but BaP-9-ol and a metabolite Mx, the structure of which has not been identified as yet, were also formed in these microsomes. Human CYP1A1 expressed with NADPH:CYP reductase (POR) in Supersomes™ oxidized BaP to the same metabolites as microsomes, but BaP-4,5-dihydrodiol has not been detected. Rat recombinant CYP1A1 in this SupersomesTM system oxidized BaP to BaP-9,10-dihydrodiol, a metabolite Mx, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione, BaP-9-ol and BaP-3-ol. Addition of cytochrome b5 to rat and human recombinant CYP1A1 systems led to a more than 2-fold increase in BaP oxidation. CONCLUSION: The results show similarities between human and rat CYP1A1 in BaP oxidation and demonstrate rats as a suitable model mimicking BaP oxidation in human.
- MeSH
- benzopyren metabolismus MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochromy b5 farmakologie MeSH
- jaterní mikrozomy účinky léků metabolismus MeSH
- karcinogeny metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- metabolická inaktivace MeSH
- oxidace-redukce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Publikační typ
- abstrakt z konference MeSH
Histone deacetylase (HDAC) inhibitors are a group of anticancer drugs which cause growth arrest and apoptosis of several tumor cells. HDAC inhibitors have been also found to increase the anticancer efficacy of several treatment modalities i.e. chemotherapy or radiotherapy. Here, we review the literature on combinations of HDAC inhibitors both with ionizing radiation and with other drugs, highlighting DNA-damaging compounds. The results of numerous studies with several types of cancer cells discussed in this review demonstrate that HDAC inhibitors enhance the effect of DNA damaging agents, such as inhibitors of topoisomerases, inhibitors of DNA synthesis, DNA-intercalators and agents covalently modifying DNA (i.e. doxorubicin, etoposid, 5-fluorouracil, cisplatin, melphalan, temozolomide and ellipticine) or of irradiation. Hence, the use of HDAC inhibitors combined with these antitumor drugs or ionizing radiation is a promising tool which may make treatment of patients suffering from many types of cancer more efficient. Several molecular mechanisms are responsible for the observed higher sensitivity of tumor cells towards therapeutic agents elicited by HDAC inhibitors. These mechanisms are discussed also in this review.
- MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- cílená molekulární terapie metody MeSH
- DNA metabolismus MeSH
- histondeacetylasy metabolismus MeSH
- inhibitory histondeacetylas chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- nádory farmakoterapie metabolismus radioterapie MeSH
- synergismus léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
