NITROAROMATICS: CARCINOGENICITY AND METABOLISM

Project: Research project

Project Details

Description

Nitropolynuclear aromatic hydrocarbons (NPAH) are widespread environmental
carcinogens which may pose a significant human health hazard.
1-Nitropyrene (1-NP) is one of the most frequently detected of the
carcinogenic NPAH and 6-nitrochrysene (6-NC) is one of the most tumorigenic
of the NAPH. It is not known whether the observed tumorigenicity of 1-NP
in newborn Sprague-Dawley rats and of 6-NC in newborn mice is due primarily
to nitroreduction, ring oxidation or a combination of both pathways. Based
on our results and those obtained by others, our hypothesis is that the
major metabolic activation pathway of 1-NP and 6-NC is ring oxidation
followed by nitroreduction. This pathway would yield several electrophilic
intermediates and multiple DNA adducts would be expected. Therefore
structural elucidation of those adducts is mandatory in order to understand
the specific role of each adduct in carcinogenesis by 1-NP and 6-NC. Thus
the proposed methods to test our hypothesis are as follows: (1) We will
establish the further metabolic transformation of known mutagenic ring
oxidized metabolites of 1-NP particularly with respect to formation of
intermediates which can bind to DNA. The structures of the major DNA
adducts formed from (3H)1-NP in rat breast (target organ), liver and colon
will be elucidated and will be compared with those formed from
(3H)1-aminopyrene and (3H)1-nitrosopyrene since the latter compounds are
weak or inactive breast carcinogens as compared to 1-NP; (2) The pattern of
6-NC metabolism and DNA adducts profiles in newborn mice will be
established and the results will be compared with those of chrysene since
the latter compound is inactive as a tumorigen in the liver and lung of
newborn mice; (3) Structural elucidation of the electrophilic intermediates
and DNA adducts derived from 1-NP and 6-NC will be based on spectral
analysis and/or independent synthesis. The results of this study are
essential in understanding carcinogenesis induced by 1-NP and 6-NC in rats
and mice respectively. In addition new DNA-adducts will be provided as
markers in order to be used in assays to study the actual exposure of
humans to 1-NP and 6-NC.
StatusFinished
Effective start/end date1/1/901/1/90

Funding

  • National Cancer Institute

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