ENZYMOLOGY AND MECHANISMS OF NITROSAMINE METABOLISM

Project Details

Description

Nitrosamines are a group of carcinogens widely occurring in the
environment. It is known that metabolic activation is required for their
carcinogenic actions. The enzymology of and factors affecting the
metabolism of nitrosamines, however, are not clearly understood. Recent
work in our laboratory has demonstrated the presence of a cytochrome P-450
(P-450)-mediated high affinity N-nitrosodimethylamine (NDMA) demethylase in
rat liver microsomes inducible by fasting, diabetes, acetone, isopropanol,
ethanol, and pyrazole. Our working hypothesis is that specific P-450
isozymes, inducible by the above factors, are responsible for the
metabolism of NDMA and probably also other nitrosamines. In this proposal
several lines of research will be pursued: 1. To purify the P-450 isozymes with high affinity and activity toward
nitrosamines from rat liver microsomes. These P-450 isozymes will be
characterized and compared with known P-450 isozymes in terms of their
substrate specificities and other molecular properties. 2. To investigate the substrate specificity and mechanisms of nitrosamine
metabolism (activation) by purified P-450 isozymes. The Km values of NDMA
demethylase as well as the nature of the oxygenation, denitrosation and
other reactions will be investigated. 3. To study the distribution and induction of the specific P-450 isozymes
as well as their roles in nitrosamine metabolism in liver and nonhepatic
tissues by immunochemical techniques and enzyme assays. 4. To illustrate the biological consequences of the induction of NDMA
demethylase by measuring in vivo DNA alkylation in different organs.
Nitrosamine metabolism in vivo and activation in model systems will be
studied to provide additional mechanistic insights into the activation
process. It is hoped that the proposed studies will yield definitive information on
the enzymology and mechanisms of nitrosamine metabolism. Such information
is crucial to our understanding of the carcinogenicity of nitrosamines and
the modification of carcinogenesis by nutritional and environmental factors.
StatusFinished
Effective start/end date2/15/841/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health: $265,655.00
  • National Institutes of Health: $236,194.00
  • 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

ASJC

  • Medicine(all)

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