QUINOLINES &BENZOQUINOLINES: MUTAGENS &CARCINOGENESIS

Project Details

Description

Quinoline, methylquinolines, and benzoquinolines are the major aza-arenes
which have been detected as pollutants in the human respiratory
environment. Our objective is to determine the mechanism(s) by which
quinoline, methylquinolines, and benzoquinolines are metabolically
activated to genotoxic agents. We will determine the mechanism by which quinoline is ultimately activated
to a hepatocarcinogen in mice and rats. It is known that rat liver
microsomes can metabolically activate quinoline to a mutagen. Our studies
on the metabolism of quinoline will be extended to include the
identification of all water-soluble metabolites formed using this
activation system. Based upon our most recent studies, the oxaziridine of
1,2-dihydroquinoline and 3,4-epoxy-3,4-dihydroquinoline are the suspect
ultimate genotoxic metabolites of quinoline. These electrophiles will be
synthesized and their biological activities evaluated relative to
quinoline. While mice and rats are known to be sensitive to the
hepatocarcinogenic effects of quinoline, hamsters and guinea pigs are
reported to be resistant. We will compare the DNA-adducts of quinoline
formed in vivo in both mice and rats with those formed in hamsters and
guinea pigs. We will structurally identify the major DNA adduct(s) of
quinoline formed in vivo. Ultimately, we will compare the metabolites of
quinoline and the DNA-adduct(s) of quinoline formed with human hepatocytes
with those formed in rat hepatocytes. Benzo(f)quinoline has been shown to be a weak hepatocarcinogen in newborn
mice. Bioassays are in progress to further evaluate the relative
carcinogenic potential of quinoline, methylquinolines, and
benzoquinolines. We will also examine the contribution of each of the
major metabolites of benzo(f)quinoline, benzo(h)quinoline, and
phenanthridine to their mutagenic activity. The major mutagenic
metabolites of these aza-arenes will also be evaluated for their
carcinogenic activity. These bicyclic and tricyclic compounds represent
the major aza-arenes which are present in the human environment. This
research is intended to increase our understanding of their genotoxic
potential as well as the molecular basis for their biological activities.
StatusFinished
Effective start/end date3/15/816/30/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $172,208.00

ASJC

  • Environmental Science(all)
  • Medicine(all)

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