Influence of beta-Naphthoflavone on 7,12-Dimethylbenz(a)anthracene Metabolism, DNA Adduction, and Tumorigenicity in Rainbow Trout
| Autor: | Ashok P. Reddy, S. Craig Stamm, David L. Alexander, George Bailey, Tracy Weimer, William Baird, Michael R. Miller, Ulrich Harttig, Jerry Hendricks |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
endocrine system
DNA Repair endocrine system diseases 9 10-Dimethyl-1 2-benzanthracene DMBA Biology Toxicology DNA Adducts Mice chemistry.chemical_compound Liver Neoplasms Experimental beta-Naphthoflavone In vivo Cytochrome P-450 CYP1A1 polycyclic compounds Animals Drug Interactions Enzyme Inhibitors skin and connective tissue diseases neoplasms Cells Cultured Carcinogen Benzoflavones 7 12-Dimethylbenz[a]anthracene Cytochrome P450 Metabolism biology.organism_classification Diet Trout Liver chemistry Biochemistry Oncorhynchus mykiss Carcinogens Microsomes Liver biology.protein Rainbow trout DNA Damage |
| Zdroj: | Toxicological Sciences. 57:217-228 |
| ISSN: | 1096-0929 |
| DOI: | 10.1093/toxsci/57.2.217 |
| Popis: | Metabolism, DNA adduction, and tumor induction by 7, 12-dimethylbenz(a)anthracene (DMBA) were examined in cultured trout liver cells and in vivo in trout. Modulating CYP1A1 activity indicated this enzyme plays a significant role in metabolizing DMBA to water-soluble compounds in isolated trout liver cells. The major DMBA metabolites identified in trout liver cells were 10-, 11-, 8,9-, and 5,6-DMBA dihydrodiols, and DMBA, 2- or 3- or 4-phenol; 7-OH-methyl-12-methyl-benz(a)anthracene and 12-OH-methyl-7-methyl-benz(a)anthracene were minor metabolites. A very small amount of DMBA-3,4-dihydrodiol was detected, and polar metabolites, which did not migrate with any DMBA metabolite standards, were observed. Incubating trout hepatocytes with DMBA-3, 4-dihydrodiol produced three prominent, nonpolar adducts indistinguishable from those in mouse embryo cells. However, DMBA-DNA adducts, formed in trout in vivo or in trout liver cells exposed to DMBA, were predominantly more polar than those formed in mouse embryo fibroblasts, and levels of DMBA-DNA adducts formed in trout liver cells were not significantly altered by modulating CYP1A1 activity. No significant repair of DMBA-DNA adducts was detected in cultured trout liver cells over a 48-h period, supporting previous studies indicating that fish are less efficient than mammals in repairing polyaromatic hydrocarbon DNA adducts. Compared to animals receiving DMBA alone, beta-naphthoflavone pretreatment in vivo did not affect hepatic CYP1A1, DMBA-DNA adducts, nor hepatic tumor response; but did significantly reduce tumor response in two other target organs. These results collectively indicate that DMBA bioactivation to DNA-binding metabolites in trout liver cells and mouse embryo cells predominantly involve different metabolic pathways to form the DNA-binding intermediates. |
| Databáze: | OpenAIRE |
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