Mechanism-based structure-carcinogenicity

Abbreviations PAH, polycyclic aromatic hydrocarbon DE, diol epoxide PAHDE, polycyclic aromatic hydrocarbon diol epoxide PAHTC, polycyclic aromatic hydrocarbon triol carbocation TC, triol carbocation BaP, benzo[a]pyrene BeP, benzo[e]pyrene BA, benz[a]anthracene DBA, dibenz[a,h]anthracene BcPh, benzo[c)phenanthrene Ch, chrysene MCh, methylchrysene MBA, 7-methyl benz[a]anthracene DMBA, 7,12-dimethyl benz[a]anthracene EBA, 7-ethyl benz[a]anthracene DB(a,l)P, dibenzo[a,l]pyrene MSCR, mechanism-based structure-carcinogenicity relationship PMO, Perturbational molecular orbital method dA, deoxyadenosine dC, deoxycytosine dG, deoxyguanosine MOS, monoxygenase enzyme system EH, epoxide hydrolase enzyme system N2(G), exocyclic nitrogen of guanine C, electrophilic centre of PAHTC K, intercalation constant CD, circular dichroism LD, linear dichroism. 

Woo YT, Lai D, McLain JL, Manibusan MK, Dellarco V (2002) Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products. Environ Health Perspect 110(suppl l) 75-87... 

Mechanism-based SAR analysis of various classes of chemical carcinogens has revealed some specific structural features that can either enhance or diminish their carcinogenic and mutagenic activities [5, 11-15, 32]. 

Lai, D.Y., Woo, Y.-T., Argus, M.F. and Arcos, J.C. (1996) Carcinogenic potential of organic peroxides prediction based on structure-activity relationships (SAR) and mechanism-based short-term tests. Environ. Carcinog. Ecotoxicol. Rev., C14, 63-80. 

There are various ways to approach SAR analysis. This chapter focuses on principles and concepts of mechanism-based SAR analysis along with an overview of the structural features and critical factors that should be considered in the evaluation of pesticides for potential carcinogenicity. Most of principles and... 

Our approach is to examine small, closely-related series of nitrosamines and to develop structure-activity models based on molecular descriptors which are explicitly meaningful with respect to the organic chemistry and biochemistry of the compounds. The forms of these models can then often be interpreted in terms of the mechanisms through which these compounds exert their carcinogenic effects. 

The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside... 

Figure 7.5 Intercalation of carcinogens into the stacked bases of nucleic acids. Both carcinogens and certain anti-neoplastic agents share a common mechanism of action. They have the capacity to insert themselves into the nucleic acid structure, causing geometrical distortions that preclnde the ability of the nucleic acid to complete its function in the processes of transcription and translation. Flat aromatic molecules have the ability to intercalate between the stacked bases.

Woo, Y.-T., Lai, D.L., Arcos, J.C., and Argus, M.F. (1984) Chemical Induction of Cancer. Structural Bases and Biologic Mechanism, Vol. IIIB, Aliphatic and Aromatic Halogenated Carcinogens, Academic Press, Orlando FL. 

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