Carcinogens, action mechanism

Thus complete intercalation of the aromatic PAH between the bases of DNA, in the manner described above for flat molecule such as proflavine, did not seem to be a likely mechanism for the carcinogenic action of these compounds. Since alkylation and intercalation are not simultaneously possible for steric reasons, and since one molecule is wedge-shaped and the other is flatter, it was considered more likely that the action of these compounds arose from their alkylating ability they could alkylate a base of DNA and then, since the bulky aromatic hydrophobic group would possibly not remain protruding into the hydrophilic environment, it is possible that the aromatic PAH group could then lie in one of the grooves of DNA. 

Kroes, R. and W. Wester. 1986. Forestomach carcinogens Possible mechanisms of action. Food Chem. Toxicol. 24 1083-1089. 

The first step, extrapolation of data from experimental animals to the human simation, is similar to the interspecies extrapolation described in detail for threshold effects (Section 5.3). The second step, evaluation of a carcinogen s mechanism(s) or mode of action(s), is very important for the choice of model for the risk assessment, i.e., non-threshold or threshold this issue is addressed in Section 4.9. The third step, quantitative dose-response assessment, is the main focus of this chapter and is addressed in more detail in the following text. 

Lutz WK, Schlatter CH. 1977. Mechanism of the carcinogenic action of benzene Irreversible binding to rat liver DNA. Chem-Biol Interact 18 241-245. 

Evidence for the mechanism of bladder cancer derives from correlation of certain structural features of aromatic amines important in carcinogenecity, and knowledge of activation steps and metabolites obtained from laboratory animals73. Earlier studies revealed the biochemistry of the carcinogenic aromatic amines Questions remained as to whether binding to DNA or RNA was causally connected to carcinogenic action. 

It is difficult to give a physicochemical meaning to AE within the framework of an action mechanism. AE is the equilibrium energy difference between the most stable "boat" and "chair" conformer states. However, suppose the production of the ultimate carcinogenic metabolite depends upon two parallel metabolic reactions as depicted in Fig. 5a. The concentration,... 

Ci, of one metabolite increases with increasing AE, while the concentration of the second metabolite, C2, decreases with increasing AE, Fig. 5b. The concentration, C3, of the ultimate carcinogen is dependent upon the produce C1C2. In this case the ultimate dependence of C3 upon AE can appear to be parabolic over some range of AE, see Fig. 5c. This explanation is not consistent with the action mechanism assumed in our modelling. Nor is there any experimental support for or against a pair of parallel metabolic reactions. However, parallel metabolic reactions can be used to account for the role of AE in eq. (9). 

Feron VJ, Til HP, de Vrijer F, et al. 1991. Aldehydes occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat Res 259 363-385. 

Dose—Response Relationships in Carcinogenesis and Mechanisms of Carcinogenic Action... 

This paper has examined the theoretical and experimental basis for the existence of different mechanisms of carcinogenic activity of chemicals within the context of the basic definition of what constitutes a carcinogenic hazard. Examined in this way, the mechanism of carcinogenic action of a chemical may encompass exposure, cell dynamics and gene activation as interrelated parts of the process of oncogenesis. The balance of these effects, or segments, of the mechanistic process define the potential carcinogenic activity of a chemical. Yet, as complex and incompletely understood in toto as this... 

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