QUINOLINES AND CARBAZOLES: MUTAGENS AND CARCINOGENS

Project Details

Description

Quinoline, carbazole, and their methylated derivatives are widely
distributed environmental pollutants and are carcinogenic in laboratory
animals. The objective of this research program is to determine the
mechanism(s) by which these aza-arenes ultimately exert their genotoxic
activity.

It is our hypothesis that quinoline is metabolically transformed to an
oxaziridine capable of interacting with DNA and other cellular
macromolecules to form adducts. The electrophilic metabolites of quinoline
formed in vivo will be investigated using radiolabeled quinoline.
Electrophilic metabolites will be identified through the analysis of the
adducts formed with glutathione and cellular macromolecules including
protein, RNA, and DNA. These biochemical studies will direct synthetic
efforts in the preparation of reference standards for comparison with the
products resulting from interaction of suspect electrophilic metabolites
with cellular macromolecules.

There are major species differences in the hepatocarcinogenic activity of
quinoline. Macromolecular adducts and metabolites formed in the liver of
rats, mice, hamsters, and guinea pigs will be analyzed to determine a
possible correlation with susceptibility. Metabolites and adducts formed
in hepatocytes from rats and humans will also be compared. Elucidation of
the mechanisms by which quinoline exerts its genotoxic activity is of
particular importance in view of these and species differences observed in
its carcinogenic activity, as well as the extent to which it is present in
the environment.

Carbazole is the second principal carcinogenic agent targeted for study in
this program. It is our hypothesis that carbazole is being transformed in
vivo to 9-hyrdoxymethylcarbazole which ultimately forms an electrophilic 9-
methiminium derivative. This hypothesis will be investigated by
characterizing the metabolites and the liver DNA adducts formed from
carbazole and 9-methylcarbazole in mice. 9-Hydroxycarbazole and 9-
acetoxycarbazole are direct-acting mutagens in S. typhimurium and extensive
adduct formation has been observed after incubation of 9-acetoxycarbazole
with DNA using the 32P-postlabeling technique. We will determine the
extent to which similar adducts are formed in vivo in mouse liver.
StatusFinished
Effective start/end date12/31/896/30/95

Funding

  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences

ASJC

  • Spectroscopy
  • Cancer Research
  • Cell Biology

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