DNA adduct formation from quaternary benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine as revealed by the 32P-postlabeling technique
Language English Country Ireland Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
12204579
DOI
10.1016/s0009-2797(02)00038-8
PII: S0009279702000388
Knihovny.cz E-resources
- MeSH
- DNA Adducts biosynthesis MeSH
- Alkaloids metabolism pharmacology MeSH
- Benzophenanthridines MeSH
- Phenanthridines metabolism pharmacology MeSH
- Antineoplastic Agents, Phytogenic metabolism pharmacology MeSH
- Intercalating Agents metabolism pharmacology MeSH
- Isoquinolines MeSH
- Microsomes, Liver drug effects metabolism MeSH
- Rats MeSH
- Quantum Theory MeSH
- Rats, Sprague-Dawley MeSH
- Phosphorus Radioisotopes analysis MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Alkaloids MeSH
- Benzophenanthridines MeSH
- chelerythrine MeSH Browser
- fagaronine MeSH Browser
- Phenanthridines MeSH
- Antineoplastic Agents, Phytogenic MeSH
- Intercalating Agents MeSH
- Isoquinolines MeSH
- Phosphorus Radioisotopes MeSH
- sanguinarine MeSH Browser
- Cytochrome P-450 Enzyme System MeSH
Using the 32P-postlabeling assay, we investigated the ability of quaternary benzo[c]phenanthridine alkaloids, sanguinarine, chelerythrine and fagaronine, to form DNA adducts in vitro. Two enhanced versions of the assay (enrichment by nuclease P1 and 1-butanol extraction) were utilized in the study. Hepatic microsomes of rats pre-treated with beta-naphthoflavone or those of uninduced rats, used as metabolic activators, were incubated in the presence of calf thymus DNA and the alkaloids, with NADPH used as a cofactor. Under these conditions sanguinarine and chelerythrine, but not fagaronine, formed DNA adducts detectable by 32P-postlabeling. DNA adduct formation by both alkaloids was found to be concentration dependent. When analyzing different atomic and bond indices of the C11-C12 bond (ring B) in alkaloid molecules we found that fagaronine behaved differently from sanguinarine and chelerythrine. While sanguinarine and chelerythrine showed a preference for electrophilic attack indicating higher potential to be activated by cytochrome P450, fagaronine exhibited a tendency for nucleophilic attack. Our results demonstrate that sanguinarine and chelerythrine are metabolized by hepatic microsomes to species, which generate DNA adducts.
References provided by Crossref.org
