Chemical reactivity as a tool to study carcinogenicity: reaction between estradiol and estrone 3,4-quinones ultimate carcinogens and guanine.
In this article we study the chemical reactions between guanine and two ultimate carcinogens, the 3,4-quinone forms of the estrogens estrone (E1) and estradiol (E2). DNA was truncated to guanine, i.e. no deoxyribose moiety was included. Due to a complex reaction that involves proton transfer via water molecules we applied linear free energy relationships rather than computation of the transition state and activation energies. The minima corresponding to reactants and products were obtained on the B3LYP/6-31G(d) level. The effects of hydration were considered using the solvent reaction field of Tomasi and co-workers and the Langevin dipoles model of Florian and Warshel. No significant difference in reaction free energy for the reaction involving estrone and estradiol metabolites was found, despite the fact that for the two substances different carcinogenic activities were reported. Differences in carcinogenicity may be therefore attributed to other types of interactions or reactions such as (i) specific interactions of the carbonyl or hydroxyl group with DNA giving rise to different activation free energies for the reactions, (ii) the reaction of depurination and subsequent effects on the DNA, (iii) enzymatic or nonenzymatic oxidation steps (P450, aromatase, peroxidases, O2) and detoxification reactions (catechol-O-methyl transferase, S-transferase), or (iv) binding of the hormone to its nuclear receptors.
Huetz
Ph
P
Laboratoire de Physique Moléculaire, UMR CNRS 6624, Faculté des Sciences et Techniques, La Bouloie, Université de Franche-Comté, 25030 Besançon, France. philippe.huetz@univ-fcomte.fr
Kamarulzaman
E E
EE
Wahab
H A
HA
Mavri
J
J
D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004958:Estradiol / Q000737:chemistry* / Q000633:toxicity*; D004970:Estrone / Q000737:chemistry* / Q000633:toxicity*; D006147:Guanine / Q000737:chemistry*; D018499:Linear Energy Transfer; D008956:Models, Chemical; D011809:Quinones / Q000737:chemistry* / Q000633:toxicity*; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D002273:Carcinogens; D011809:Quinones; D012996:Solutions; D004970:Estrone; D004958:Estradiol; D006147:Guanine; D004247:DNA