In Vivo Formation and Persistence of Modified Nucleosides Resulting from Alkylating Agents

Abstract

Alkylating agents are ubiquitous in the human environment and are continuously synthesized in vivo. Although many classes exist, interest has been focused on the N-nitroso compounds, since many are mutagens for bacteria, phage, and cells, and carcinogens for mammals. In contrast to aromatic amines and polyaromatic hydrocarbons which can react at carbons, simple alkylating agents react with nitrogens and oxygens: 13 sites are possible, including the internucleotide phosphodiester. However, only the Nnitroso compounds react extensively with oxygens. In vivo, most possible derivatives have been found after administration of methyl and ethyl nitroso compounds. The ethylating agents are more reactive toward oxygens than are the methylating agents and are more carcinogenic in terms of total alkylation. This is true regardless of whether or not the compounds require metabolic activation. It has been hypothesized that the level and persistence of specific derivatives in a "target" cell correlates with oncogenesis. However, no single derivative can be solely responsible for this complex process, since correlations cannot be made for even a single carcinogen acting on various species or cell types. Some derivatives are chemically unstable, and the glycosyl bond is broken (3-and 7-alkylpurines), leaving apurinic sites which may be mutagenic. These, as well as most adducts, are recognized by different enzymatic activities which remove/ repair at various rates and efficiencies depending on the number of alkyl derivatives, as well as enzyme content in the cell and recognition of the enzyme. Evaluation of human exposure requires early and sensitive methods to detect the initial damage anid the extent of repair of each of the many promutagenic adducts.

Evaluation of the in vivo mutagenicity of isopropyl methanesulfonate in acute and 28‐day studies

“…Due to their short half‐ life, N 7 adducts are unstable and therefore non‐mutagenic [Boysen et al, ]. In contrast, O 6 adducts are known to produce pro‐mutagenic lesions [Singer, ; La and Swenberg, ; Hemminki et al, ]. Therefore, alkylating agents that have a S N 2 mechanism would be expected to produce mainly N 7 adducts, which would be more likely to result in a sublinear response being observed at higher doses given the weakly mutagenic nature.…”

DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans

“…Common environmental and dietary chemical carcinogens include PAHs, nitro‐PAHs, nitrosamines, aflatoxins, mustards, aromatic amines, heterocyclic aromatic amines (HAAs), methylating agents, other alkylating agents, and haloalkanes . DNA adducts of these carcinogens can be formed at different ring nitrogen atoms, and exocyclic nitrogen and oxygen atoms of the nucleobases including the N 7, N 3, N 2 , N 1, and O 6 positions of guanine, the N 7, N 6 , N 3, and N 1 positions of adenine, the N 3, N 4 , and O 2 positions of cytosine, and the N 3, O 2 , and O 4 positions of thymine (Figure ).…”

Μηχανισμοι Γενοτοξικοτητας Αλκυλιωτικων Κυτταροστατικων Παραγοντων

“…Οι αλκυλιωτικοί παράγοντες αποτελούν μια κατηγορία χημικών ουσιών που έχουν κοινό γνώρισμα ότι προκαλούν αλκυλίωση σε βιολογικά μακρομόρια (δηλαδή, μεταφορά μιας σχετκά μικρής χημικής ομάδας π.χ. μεθυλο-ή αιθυλο- Kus'mierk 1982, Singer 1985).…”

“…Μία άλλη ομάδα βιολογικά σημαντικών αλκυλιωτικών παραγόντων είναι και οι αλλονιτρωδοουρίες, που περιλαμβάνουν παράγοντες τόσο με αντινεοπλασματική όσο και μεταλλαξιγόνο δράση (Singer et Kus'mierk 1982, Ludlum 1990). Έχει δειχθεί ότι οι αλλονιτρωδοουρίες προκαλούν τριών ειδών τροποποιήσεις: 1) υποκατάσταση βάσης 2) τροποποιήσεις που περιλαμβάνουν το σχηματισμό ενός επιπρόσθετου ετεροκυκλικού δακτυλίου και 3) τροποποιήσεις που περιλαμβάνουν σταυροδεσμούς μεταξύ δύο βάσεων (Ludlum 1990).…”

“…Θέσεις αντίδρασης των απλών αλκυλιωτικών παραγόντων με τα νουκλενικά οξέα ή τα πολυνουκλεοτίδια(Singer 1982).7-χλωροαιθυλογουανίνη και 7-υδροξυαιθυλογουανίνη σε μεγάλο βαθμό. Η BCNU [1,3-δις(2χλωροαιθυλ)-1-νιτρωδοουρία] φαίνεται να αντιδρά με το DNA με τρεις διαφορετικούς τρόπους σχηματίζοντας αλλοαιθυλο-, υδροξυαιθυλο-και αμινοαιθυλο-τταράγωγα όλα στη Ν7 θέση της γουανίνης (Singeret Kus'mierk 1982).…”