Influence of Beta-Naphthoflavone on 7,12-Dimethylbenz(a)anthracene Metabolism, DNA Adduction, and Tumorigenicity in Rainbow Trout

Details

• Personal Author:
  Alexander D ; Bailey G ; Baird W ; Harttig U ; Hendricks J ; Miller MR ; Reddy AP ; Stamm SC ; Weimer TL
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Digestive System Digestive System Diseases Embryology Endotoxins Genetics Liver Neoplasms Occupational Health Safety
• Keywords:
  Analytical-methods Analytical-processes Animal-studies Cell-biology Cell-metabolism Cell-transformation Embryopathology Embryotoxicity Genes Genetic-factors Genotoxic-effects Hepatocytes Hepatotoxicity Hepatotoxins Liver-cells Liver-disorders Liver-tumors Organs

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Oregon ; OSHA Region 10 ; OSHA Region 3 ; OSHA Region 5 ; West Virginia ; Wisconsin
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  217-228
• Volume:
  57
• Issue:
  2
• NIOSHTIC Number:
  nn:20032338
• Citation:
  Toxicol Sci 2000 Oct; 57(2):217-228
• Contact Point Address:
  MR Miller, Department of Biochemestry, West Virginia University Health Sciences Center, POB 9142, Morgantown, WV 26506
• Email:
  mmiller@hsc.wvu.edu
• Federal Fiscal Year:
  2001
• Peer Reviewed:
  True
• Source Full Name:
  Toxicological Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:9f35061a8f7c1fe64980668ec9f8f66a4f2e709c54e4f1111ba4d8e2088de7627f2c6cc049b989955edbdacad435a12ac6e3804b7b7e09e8abbc32b34f3d0eac
• Download URL:
  https://stacks.cdc.gov/view/cdc/186356/cdc_186356_DS1.pdf
• File Type:
  [PDF - 206.55 KB ]