ENVIRONMENTAL POLYCYCLICS: METABOLISM AND ACTIVATION

Project Details

Description

The objective of this proposal is to determine the modes of metabolic
activation of the carcinogenic non-alternate polynuclear aromatic
hydrocarbon carcinogens benzo-(b)fluoranthene, benzo(j)fluoranthene,
benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene, and 2- and
3-methylfluoranthene. The bay region theory of activation of carcinogenic
PAH has been shown to apply to several alternate hydrocarbons. Our studies
on the metabolic activation of these six non-alternate PAH indicate that
there is little or no similarity in their activation pathways. This
program has as its overall objective to elucidate the mechanism of
activation of these select PAH which are of particular interest because of
actual human exposure.

Suspect proximate and/or ultimate carcinogenic metabolites of
benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene and 2-
and 3-methylfluoranthene have been identified from detailed in vitro and in
vivo metabolism studies. Those metabolic activation pathways believed to
be associated with carcinogenic activity of these PAH will be evaluated by
identification of major DNA-adducts formed in vivo in mouse skin, bioassays
of suspect proximate and ultimate mutagens, and/or bioassays of select
fluoro-substituted analogs. Studies on the metabolic activation of
benzo(b)-fluoranthene suggest that multiple sites on this molecule are
associated with its carcinogenicity. Fluorescence spectra of isolated DNA
adducts as formed in vivo in mouse skin and a limited study on the effect
of fluoro-substitution at specific positions of benzo(b) fluoranthene on
tumorigenic activity will be employed to elucidate the mechanism(s) of
activation associated with its carcinogenicity.

These studies will lead to the elucidation of the mechanism of action of
several of these carcinogenic non-alternate PAH, which are ubiquitous in
the environment.
StatusFinished
Effective start/end date12/31/8912/31/89

Funding

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

ASJC

  • Cancer Research

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