The effect of benzo[a]pyrene on metabolic activation of anticancer drug ellipticine in mice
Language English Country Sweden Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
14329
Cancer Research UK - United Kingdom
PubMed
24362092
PII: NEL341013A07
Knihovny.cz E-resources
- MeSH
- Antineoplastic Agents pharmacokinetics MeSH
- Benzo(a)pyrene pharmacology MeSH
- Biotransformation drug effects MeSH
- Cytochrome P-450 CYP1A1 metabolism MeSH
- Cytochrome P-450 CYP1A2 metabolism MeSH
- Ellipticines pharmacokinetics MeSH
- Microsomes, Liver drug effects metabolism MeSH
- Drug Interactions MeSH
- Mice, Inbred C57BL MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Drug Evaluation, Preclinical MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- Benzo(a)pyrene MeSH
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1A2 MeSH
- Ellipticines MeSH
- ellipticine MeSH Browser
- Cytochrome P-450 Enzyme System 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.
