Elsevier

Toxicology

Volume 166, Issues 1–2, 14 September 2001, Pages 31-36
Toxicology

New DNA adducts of crotonaldehyde and acetaldehyde

https://doi.org/10.1016/S0300-483X(01)00436-XGet rights and content

Abstract

This paper summarizes our recent studies on adducts produced in the reactions of the carcinogens crotonaldehyde (2-butenal) and acetaldehyde with deoxyguanosine (dG) and DNA. Human exposure to these carcinogens can be considerable, from both exogenous and endogenous sources. Crotonaldehyde reacts with DNA to form Michael addition products, a pathway that has been well described. We describe a second major pathway, in which 3-hydroxybutanal, formed by addition of H2O to crotonaldehyde, reacts with DNA to produce the Schiff base N2-(3-hydroxybut-1-ylidene)dG as well as several diastereomers of N2-paraldol-dG. Acetaldehyde reacts with DNA and dG giving a major Schiff base adduct, N2-ethylidene-dG. A cross-linked adduct of acetaldehyde has been characterized for the first time, and other adducts resulting from the reaction of two and three molecules of acetaldehyde with dG have been observed. The results of these studies demonstrate that some structurally unique adducts are formed from these carcinogenic aldehydes and suggest some new directions for research on the potential role of aldehydes in human cancer.

Introduction

It is a pleasure to write this manuscript in commemoration of John H. Weisburger's 80th birthday. I first met John in 1973, shortly after he, along with Dietrich Hoffmann and Ernst Wynder, had recruited me to the American Health Foundation, which at that time was a fledgling organization. John had only recently joined the Foundation, beginning his second career after many successful years at the National Cancer Institute. I could not help but be impressed by his optimism, a quality that was very important in the success of the American Health Foundation during John's tenure as Director of Research.

In one of the early internal seminars held at the Foundation, John described the electrophilic reactant hypothesis of carcinogen–DNA binding, an area that was rapidly developing at that time, and to which he and Elizabeth Weisburger had made important contributions through their work on aromatic amine metabolism. This hypothesis was appealing to me as an organic chemist, and I began to think about research in this area.

At the same time, Dietrich Hoffmann had begun his initial studies on the carcinogen N′-nitrosonornicotine (NNN) (Fig. 1) in tobacco, an area in which I was fortunate to become a collaborator. Dietrich encouraged me to investigate the metabolism of NNN, and I pursued this area actively in context of the electrophilic reactant hypothesis. In parallel, my group began studies on the metabolism and DNA binding of the hepatocarcinogen N-nitrosopyrrolidine (NPYR) (Fig. 1) because it was structurally related to NNN. Our work on NPYR revealed that one of its electrophilic metabolites was in fact crotonaldehyde (2-butenal), and that these two carcinogens formed some common DNA adducts (Chung and Hecht, 1983, Wang et al., 1988). Research on crotonaldehyde in turn convinced us that there might be some common DNA adducts of crotonaldehyde and acetaldehyde, which is the topic of the present manuscript.

Section snippets

DNA adducts of crotonaldehyde

Crotonaldehyde (1, Scheme 1) is a mutagen and carcinogen (International Agency for Research on Cancer, 1995). Crotonaldehyde causes liver tumors when administered to rats in the drinking water (Chung et al., 1986). It is a common environmental contaminant, detected in mobile source emissions, tobacco smoke, and other combustion mixtures (International Agency for Research on Cancer, 1995). It is a product of lipid peroxidation, and studies by Chung and co-workers have identified

DNA adducts of acetaldehyde

Acetaldehyde causes mutations, sister chromatid exchanges, micronuclei and aneuploidy in cultured mammalian cells. It is carcinogenic in rats and hamsters, inducing tumors of the respiratory tract after administration by inhalation. Acetaldehyde occurs widely in the human environment as a pyrolysis product and as a natural constituent of foods (International Agency for Research on Cancer, 1985; International Agency for Research on Cancer, 1999). Its concentration in tobacco smoke, 920 μg per

Conclusions

The results of these studies provide new insights pertinent to determining the role of aldehydes as human carcinogens. We have described several new DNA adducts of crotonaldehyde and acetaldehyde; adducts are also formed from the related compounds aldol, aldoxane, and paraldol. It will be important to determine the amounts of these adducts in human DNA. The cross-linked adduct 3 as well as diastereomers of N2-paraldol-dG and N2-aldoxane-dG warrant further investigation with respect to the

Acknowledgements

The authors thank John Weisburger for his enthusiastic and constant support of our research goals. This research was supported by grant number CA-85702 from the National Cancer Institute. They also thank Guang Cheng, Yongli Shi, and Peter W. Villalta for their contributions to this research.

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