Nitrosamino Fragmentation and Nitrosamine Carcinogenesis

Loeppky, Richard

Abstract

A great deal of recent evidence suggests that nitrosamines are activated to ultimate carcinogens by a set of sequential and perhaps competing biochemical transformations. Our recent work has elucidated the characteristics of a chemical model reaction which cleaves a beta-hydroxy-nitrosamine to a smaller fragment nitrosamine. We have shown that rat lines S-9000 fraction is capable of producing an analogous biochemical fragmentation of the nitrosamine Calpha-Cbeta bond. The proposed research deals with the elucidation of this interesting biochemical chain shortening transformation, and model chemical experiments which are planned to give more insight into optional bioactivation routes for beta-hydroxy and beta-keto nitrosamines. Sensitive chemical analytical methods will be developed for detecting this retroaldol-like fragmentation reaction. The biological conditions for observing the transformation will be optimized and the active cell fraction located. Structurally varied nitrosamines will be used to determine structure-activity relationships. Various tissues types will be examined for their ability to produce the transformation. Model chemical experiments will be performed to explore the possibility that certain beta-nitrosamino aldehydes exhibit chemical properties expected of direct acting carcinogens and that the biochemical oxidation of a primary nitrosamino alcohol could constitute suitable activation to produce carcinogensis. It is proposed that the one electron oxidation or reduction of an appropriate beta-oxidized nitrosamine could lead to reactive radicals and could provide an alternative biochemical activation route. A study of this possibility using a chemical model system is planned. Similarly, the activity of vinyl nitrosamines, products of environmental beta-hydroxynitrosamines, toward biological nucleophiles will be examined in chemical model experiments to determine if this route can result in DNA/RNA or protein alteration relevant to carcinogenesis. It is hoped that this work may result in possible means of inhibiting certain nitrosamine biological activation routes related to carcinogenesis.