Abstract
Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens—widely detectable in relatively low levels in food, water, cosmetics, and drugs—are well-established and powerful animal carcinogens. The electrophiles resulting from the cytochrome P450-mediated metabolism of N-nitrosamines can readily react with DNA and form covalent addition products (DNA adducts) that play a central role in carcinogenesis if not repaired. In this review, we aim to provide a comprehensive and updated review of progress on the metabolic activation and DNA interactions of 10 carcinogenic N-nitrosamines to which humans are commonly exposed. Certain DNA adducts such as O6-methylguanine with established miscoding properties play central roles in the cancer induction process, whereas others have been linked to the high incidence of certain types of cancers. We hope the data summarized here will help researchers gain a better understanding of the bioactivation and DNA interactions of these 10 carcinogenic N-nitrosamines and facilitate further research on their toxicologic and carcinogenic properties.
| Original language | English (US) |
|---|---|
| Article number | 4559 |
| Journal | International journal of molecular sciences |
| Volume | 23 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2022 |
Bibliographical note
Funding Information:and Relevance to Human Cancer, sponsored by the International Agency for Research on Cancer (IARC), Agriculture Canada, and the Alberta Heritage Foundation for Medical Research in Banff, (IARC), Agriculture Canada, and the Alberta Heritage Foundation for Medical Research in Banff, Canada, 5–9 September 1983. (Reprinted with permission of the IARC). All N-nitrosamines require metabolism to exert their carcinogenic properties. The 2. Overview of Carcinogenic N-Nitrosamines to Which Humans electrophiles produced in these simple metabolic pathways, generally catalyzed by cyto-Are Commonly Exposed chrome P450 enzymes, readily alkylate DNA initiating the carcinogenic process. These N-Nitrosamines are the products of nitrosation reactions occurring on the N atoms critical pathways are the subject of this review of the 10 N-nitrosamines illustrated in Fig-of secondary and tertiary amines. They can be formed during water and food processing, ure 1. tobacco curing, and drug and cosmetics manufacturing; they can also be formed endogenously. The compounds shown in Figure 1 represent an important family of carcinogens thatposedare closely related to our daily lives [9,11].
Funding Information:
Funding: Financial support for tobacco-specific N-nitrosamine studies in our laboratory was provided by the U.S. National Cancer Institute through grant CA-81301. Mass spectrometry was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, funded in part by Cancer Center Support grant CA-77598.
Publisher Copyright:
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Keywords
- DNA adducts
- N-nitrosamines
- NDMA
- P450s
- metabolism
