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J. Chem. Inf. Comput. Sci. 2004, 44, 310-314
Chemical Reactivity as a Tool To Study Carcinogenicity: Reaction between Estradiol
and Estrone 3,4-Quinones Ultimate Carcinogens and Guanine†
Ph. Huetz,*,‡ E. E. Kamarulzaman,§ H. A. Wahab,§ and J. Mavri*,‡,| Laboratoire de Physique Mole´culaire, UMR CNRS 6624, Faculte´ des Sciences et Techniques, La Bouloie, Universite´ de Franche-Comte´, 25030 Besanc¸on Cedex, France, and School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia 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. nodeoxyribose moiety was included. Due to a complex reaction that involves proton transfer via water moleculeswe applied linear free energy relationships rather than computation of the transition state and activationenergies. 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 theLangevin dipoles model of Florian and Warshel. No significant difference in reaction free energy for thereaction involving estrone and estradiol metabolites was found, despite the fact that for the two substancesdifferent carcinogenic activities were reported. Differences in carcinogenicity may be therefore attributed toother types of interactions or reactions such as (i) specific interactions of the carbonyl or hydroxyl groupwith DNA giving rise to different activation free energies for the reactions, (ii) the reaction of depurinationand 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) bindingof the hormone to its nuclear receptors.
ment therapy and estrogens’ link to breast cancer (Women’sHealth Initiative,10,11 Million Women Study12). As is the case Carcinomas are associated with chemical modifications for polyaromatic hydrocarbons, hormones themselves are not of nucleic acids. Damages can be produced by synthetic or carcinogenic, but, aside from an effect which could result natural chemicals such as (poly)aromatic hydrocarbons or from binding to their nuclear receptors, they have to be aflatoxins,1 free radicals, or reactive oxygen species which activated to reactive metabolites to be cancer initiators.
can be issued from photochemical reactions or enzyme Indeed, endogenous estrogen (E) metabolites, through cat- activity. Oncogenes are altered versions of genes implied in echol estrogens (CE) formation, have been shown to exhibit cellular growth and division, which can be of cellular or viral genotoxic properties which can lead to carcinogenic DNA origin. A significant proportion of carcinoma is believed to mutations.13 They can be oxidized to two types of o-quinones originate from environmental factors.2 Carcinogenicity of (Q) which bind to DNA giving either stable adducts, in the polyaromatic compounds has been the subject of many case of E-2,3-Q, or depurinating adducts in the case of E-3,4- experimental and computational studies.3-9 Polyaromatic Q.14 In the latter, these adducts, formed at N7 of guanine15 compounds are not carcinogenic per se and are called or at N3 of adenine,16 are lost from DNA by presumable procarcinogens, whereas their metabolites are carcinogenic cleavage of the glycosidic bond, leaving apurinic sites which and are called ultimate carcinogens.
are tumor-initiating in a number of human cancers. However, Nevertheless a certain class of procarcinogens is inherent the 2-hydroxylation of estrogens pathway might not be to to the human body. This includes steroid hormones that have neglect.17 Some xenobiotics, such as dioxin, aromatic a partial aromatic structure. Carcinogenesis associated with hydrocarbons, or pesticides, influence the expression level this class of compounds is called endogeneous, and indeed of cytochromes P450. Indeed dioxin, as well as xenoestro- hormonal carcinogenesis is believed to be responsible for a gens, lead to the diminution of the expression of CYP1A1 number of cancers, such as ovary, uterus, mammary gland, and not CYP1B1, which could unbalance production of and prostate. In particular, a serious controversy is at its catechols in favor of 4OH-E, associated with a higher height with regard to the inherent risks of hormone replace- † Dedicated to George W. A. Milne, a long-term editor of JCICS, our The level of carcinogenicity of E-3,4-Q seems to be highly dependent on the species and type of tissue (e.g. human breast,19 hamster kidney,20 rat mammary gland, or prostate21).
[email protected] (P.H.) and phone: In B6C3F1 mice liver for instance, E1-3,4-Q (estron derived | On leave from National Institute of Chemistry, Hajdrihova 19, 1000 quinone) was very carcinogenic and toxic, whereas E2-3,4-Q (estradiol derived quinone) was not, which is not understood yet.14 In SENCAR mice skin, E2-3,4-Q could be at the origin J. Chem. Inf. Comput. Sci., Vol. 44, No. 2, 2004 311
Figure 1. Reaction between guanine and E1 or E2-3,4-Q, following a Michael reaction mechanism.
2.1. In Vacuo Calculations. In vacuo calculations were
performed on a semiempirical MO level PM3 and a DensityFunctional Theory (DFT) level B3LYP. Both methodsproved to be efficient for describing chemical processes insystems of biological interest. DFT calculations were per-formed using the basis set 6-31G(d). The double-zeta basisset augmented with polarization functions on the heavy atomsis flexible enough to faithfully describe chemical processes Figure 2. DFT optimized structures of 4-hydroxy-estradiol-1-N7
while being still computationally tractable. Since the systems guanine (left) and 4-hydroxy-estrone-1-N7 guanine (right) adducts.
studied are relatively large, the applied DFT level is a goodcompromise between quality of the results and CPU effort.
of oncogenic H-ras mutations due to DNA depurination by Initial structures were obtained by model building using the a predominant rapidly depurinating 4-hydroxy E2-N3 adenine adduct.22 In calf thymus with the inclusion of Cu(II) and The structures corresponding to estradiol in the 3,4- NADPH, single strand breaks as well as aldehydic lesions quinone form, estron in the 3,4-quinone form, guanine, and were induced in the DNA for both E2-3,4-Q and E2-2,3-Q.23 products of both ultimate carcinogens with guanine were built Oxidation of estrogens to the quinone forms is catalyzed and the geometries were optimized on the PM3 level, by cytochrome P450 and different peroxidases. P450 type followed by geometry optimization on the DFT level. Thus is important for the specific enzyme activity, which may for geometry optimizations were applied to all reactants and instance favor the formation of 16R-hydroxylated estrogens, products. Vibrational analysis was performed in the harmonic also chemically reactive and potentially mutagenic.24 COMT approximation to prove that the minima are real minima (catechol-O-methyltransferase) plays a crucial role in lower- rather than saddle points. In addition we also calculated the ing the potential for DNA damage, through methylation of zero point energy corrections in the harmonic approximation.
catechol estrogens into inactive methoxyestrogens, which in 2.2. Hydration Free Energies. To calculate free energies
return can exert feedback inhibition of P450.25 The detoxi- of hydration for the studied species we applied two methods.
fying S-transferase lowers the levels of CE-Q through The first is the PCM solvent reaction field method of Tomasi formation of conjugates with glutathione.A common feature and co-workers applying a realistic cavity shape. The solute of ultimate carcinogens is their electrophilicity. As such they cavity is composed of interlocking spheres. For a review see can easily attact DNA and in particular guanine at position ref 27. The applied PCM method is closely related to the N7 or adenine at position N3. To our best knowledge, the solvation model developed by Baldridge and co-workers.31 only computational study up to now dealing with carcino- The Langevin dipoles method calculates the free energy of genicity of estrogens was the contribution of Picazo and hydration as the reversible work necessary for embeddingthe solute described by a set of point charges to the grid of Salcedo,26 who addressed the difference in carcinogenicity the Langevin dipoles, together with a proper parametrization.
of the two procarcinogens estrone and estradiol using DFT By displacing the solute (50 times in our calculations), calculations, with no DNA target included. They concluded thermal averaging is performed and the main lack of the that the difference in carcinogenicity can be attributed to the solvent reaction field is in this way overcome. DFT and difference in electrostatic potential and to the fact that estrone semiempirical MO calculations were run with a Gaussian- has more aromatic character than estradiol.
0332 suite of programs. Langevin dipole calculations were In this work we addressed by using DFT calculations the performed using CHEMSOL versions 1.1 and 2.1 packages chemical reaction between either estrone or estradiol 3,4- kindly provided by Jan Floria´n.33,34 We followed the authors’ quinone ultimate carcinogens and guanine, taken as a model recommendation to use Merz-Kollman charges calculated for DNA, forming the 4-hydroxy(E1 or E2)-1-N7 guanine at the HF/6-31G(d) level for CHEMSOL 1.1, while for adducts. The subsequent reaction involving depurination was version 2.1 charges were calculated at the B3LYP/6-31G(d) not considered. The geometries of the reactants and products level with an included solvent reaction field. The HF/6-31G- were optimized in vacuo first at the semiempirical PM3 level (d) wave function exaggerates with predicted dipole mo- and refined at DFT B3LYP level. Hydration free energies ments, what corresponds to the situation of polarized wave were calculated using either the PCM solvent reaction field function in solution. All calculations were performed on a method of Tomasi and co-workers27 or the Langevin dipoles cluster of dual-CPU PC/Linux processors (AMD Athlon XP method of Florian and Warshel.28,29 Activation free energy for each reaction was estimated using the linear free energy 2.3. Linear Free Energy Relation. The studied reactions
are electrophilic substitutions and are associated with a 312 J. Chem. Inf. Comput. Sci., Vol. 44, No. 2, 2004
Table 1. Free Energy and Free Energy Components for Reactions
Solvation free energies were modeled on three levels. All between Estron and Estradiol in Their 3,4-Quinone Form (E1-3,4-Q three methods predict no substantial difference between and E2-3,4-Q, Respectively, i.e. Ultimate Carcinogens) and Guanineg hydration free energy contributions for the reactions. Our calculations give strong evidence that in the guanine alky- lation step there is no difference in E1 and E2 quinones reactivity. Linear free energy relation is an established and widely used method in physical organic chemistry, and we B3LYP/6-31G(d) calculated gas-phase energies. b B3LYP/6-31G(d) see no reason it would not work in our case. We believe calculated zero point energy (ZPE) corrections. The ZPE was calculatedas ZPE(product) - ZPE(reactants). c Free energy of hydration differ- that inclusion of an explicit or even a chemically reactive ences was obtained using Langevin dipoles (LD) method with ChemSol solvent, for example on Car-Parrinello level, while keeping 1.1 parametrization. Merz-Kollman charges were calculated using HF/ truncation of DNA to guanine would not change the results.
6-31G(d) wave function (gas phase) applied to the B3LYP/6-31G(d) We can conclude that both chemical reactions leading to optimized geometry. d Free energy of hydration differences wasobtained using PCM solvent reaction field of Tomasi in conjunction guanine alkylation have not significantly different free with HF/6-31G(d) wave function. e LD free energy of hydration energies of reaction and that the corresponding rate constants differences using ChemSol 2.1 parametrization, where Merz-Kollman charges were calculated at B3LYP/6-31G(d) level using Tomasi’s PCMSCRF. f Reaction free energy ∆G How can then observed possible differences in carcino- feel that the LD method with ChemSol 2.1 parametrization is the most genicity of both estrogens be addressed? We offer more reliable. g (Free) energy of reaction was calculated as (free) energy of possible answers. One reason could be that DNA modeled the product (adduct with guanine) minus (free) energy of reactants.
by guanine is truncated too much, and specific interactions All (free) energies are in kcal/mol.
between DNA and the carbonyl or hydroxyl group in E1 or complex mechanism involving proton transfer via several E2-3,4-Q, respectively, might affect the chemical reactivity.
solvent molecules. Location of a transition state and calcula- From the computational point of view this limitation could tion of activation free energy for such a complex reaction is be overcome by extending the system and/or using QM/MM not practical. In the present case we are dealing with two methods that are developed and ready to be used. Another closely related reactants since the two estrogen ultimate possible explanation is linked to the fact that E1 and E2 carcinogens only differ in a carbonyl or hydroxyl group being undergo other metabolic transformations at different rates.
at a large topological distance from the reactive carbon atom.
In particular reactions catalyzed by enzymes such as catechol- The linear free energy relation seems to be the method of O-methyl transferase (COMT), glutathione-S-transferase, choice to estimate the activation free energy. The method is P450 (CYP families), aromatase, or peroxidases play a key empirical and states that in a series of chemical reactions role uphill from the reaction we considered, and the synthesis involving similar reactants and having the same mechanism, of the estrogens genotoxic metabolites depends on the the reaction with the most favorable reaction free energy will expression and activity levels of these enzymes. For instance, have the lowest free energy of activation. The rationale evidence is given that the genotype of COMT is linked to behind this is that if one approximates reactant and product breast carcinogenesis.36 (See also ref 37 for a review of free energy hypersurface wells with parabolas, they are genetic polymorphisms and breast cancer risk.) Endogenous expected to have about the same curvatures since we are estrogens themselves are able to modify the activity of the dealing with similar species. Clearly, the point of their enzymes producing their metabolites. In fact, the most intersection will be lower if the product parabola is lower, frequently evoked mechanism in the development of some giving rise to lower activation free energy for the reaction.
cancers due to estrogens prolonged exposure is the stimula- Application of linear free energy relationships in enzyme tion of cellular growth by chronic activation of estrogens catalysis is well established and is described in ref 35.
receptors. Thus, the biochemistry of these receptors isimportant to consider for a difference in E1 and E2 carcino- genic effects. In addition to all these possibilities, one hasto remember that not only DNA but proteins are also targets The free energies for both reactions as well as their for reactions with quinones,38 as well as cellular lipids and components are collected in Table 1. It is clear that there is some metallic ions (iron and copper).39 Finally, we would no significant difference between reaction free energies forthe reactions of both carcinogens with guanine. Neither in like to draw attention to another candidate reaction where vacuo values of energies differ from each other nor the the reaction rates may differ, i.e. depurination of the adducts contributions from hydration free energies within each through cleavage of the chemical bond between deoxyribose method of calculation. Interestingly, we noticed that use of the semiempirical method PM3 yielded the same in vacuo All in all, steroid hormone induced carcinogenesis is results, providing reaction enthalpies of -17.36 and -17.13 associated with an extremely complex set of biochemical kcal/mol for E1-3,4-Q and E2-3,4-Q, respectively. This gives transformations. The fact that 31 different metabolites of additional proof that the in vacuo contribution to the reaction estrogens were identified in the mammary gland carcinoma free energy is basically identical for both reactions. We tissue40 tells enough about the complexity of the reactions.
believe that the applied DFT level is reliable, and we checked We believe that those processes must be better understood the obtained stationary points to be minima rather than saddle at the molecular level and more particularly under the points by performing vibrational analysis in the harmonic physicochemical point of view. The methods for modeling approximation for all the species. The calculated zero point chemical reactions in solution are developed and ready to contributions to reaction free energies for both reactions are be used. We are sure that molecular modeling of chemical reactivity will play an important role in cancer research and J. Chem. Inf. Comput. Sci., Vol. 44, No. 2, 2004 313
will finally contribute to improve the prevention and the Estradiol-3,4-quinone in vitro and in Female ACI Rat Mammary Gland in vivo. Carcinogenesis 2003, in press.
(17) Mesia-Vela, S.; Sanchez, R. I.; Li, J. J.; Li, S. A.; Conney, A. H.; Kauffman, F. C. Catechol Estrogen Formation in Liver Microsomes from Female ACI and Sprague-Dawley Rats: Comparison of 2- and
4-Hydroxylation Revisited. Carcinogenesis 2002, 23, 1369-1372.
P.H. is grateful to the Ligue du Doubs contre le Cancer (18) Coumoul, X.; Barouki, R. Ge´notoxicite´ des me´tabolites des oestroge`nes of France for financial support of this work. J.M. gratefully et cancers. Me´decine/Sciences 2002, 18, 86-90.
(19) Markushin, Y.; Zhong, W.; Cavalieri, E. L.; Rogan, E. G.; Small, G.
acknowledges the Ministry of Science and Technology of J.; Yeung, E. S.; Jankowiak, R. Spectral Characterization of Catechol the Republic of Slovenia for financial support. J.M. would Estrogen Quinone (CEQ)-Derived DNA Adducts and their Identifica- like to thank University of Sains Malaysia for hospitality tion in Human Breast Tissue Extract. Chem. Res. Toxicol. 2003, 16,
1107-1117.
during his stay in Penang where this work was initiated and (20) Devanesan, P.; Todorovic, R.; Zhao, J.; Gross, M. L.; Rogan, E. G.; the Laboratoire de Physique Mole´culaire of the University Cavalieri, E. L. Catechol Estrogen Conjugates and DNA Adducts in of Franche-Comte´ in Besanc¸on (France) for visiting profes- the Kidney of Male Syrian Golden Hamsters Treated with 4-hydroxy- estradiol: Potential Biomarkers for Estrogen-initiated Cancer. Car-
cinogenesis
2001, 22, 489-497.
(21) Cavalieri, E. L.; Rogan, E. G. A Unified Mechanism in the Initiation of Cancer. Annals N.Y. Acad. Sci. 2002, 959, 341-354.
(22) Chakravarti, D.; Mailander, P. C.; Li, K. M.; Higginbotham, S.; Zhang, (1) Smela, M. E.; Hamm, M. L.; Henderson, P. T.; Harris, C. M.; Harris, H. L.; Gross, M. L.; Meza, J. L.; Cavalieri, E. L.; Rogan, E. G.
Evidence that a Burst of DNA Depurination in SENCAR Mouse Skin Adduct Plays a Major Role in Causing the Types of Mutations Induces Error-prone Repair and Forms Mutations in the H-ras Gene.
Observed in Human Hepatocellular Carcinoma. Proc. Natl. Acad. Sci. Oncogene 2001, 20, 7945-7953.
U.S.A. 2002, 99, 6655-6660.
(23) Lin, P.-H.; Nakamura, J.; Yamaguchi, S.; Asakura, S.; Swenberg, J.
(2) In General and Systematic Pathology, 3rd ed.; Underwood, J. C. E., A. Aldehydic DNA Lesions Induced by Catechol Estrogens in Calf Ed.; Churchill Livingstone: Edinburgh, 2000.
Thymus DNA. Carcinogenesis 2003, 24, 1133-1141.
(3) Sayer, J. M.; Yagi, H.; Wood, A. W.; Conney, A. H.; Jerina, D. M.
(24) Lee, A. J.; Conney, A. H.; Zhu, B. T. Human Cytochrome P450 3A7 Extremely Facile Reaction between the Ultimate Carcinogen Benzo- has a Distinct High Catalytic Activity for the 16R-Hydroxylation of [a]pyrene-7,8-diol 9,10-Epoxide and Ellagic Acid. J. Am. Chem. Soc. Estrone but not 17 -Estradiol. Cancer Res. 2003, 63, 6532-6536.
1982, 104, 5562-5564.
(25) Dawling, S.; Roodi, N.; Parl, F. F. Methoxyestrogens Exert Feedback (4) Sayer, J. M.; Chadha, A.; Agarwal, S. K.; Yeh, H. J. C.; Yagi, H.; Inhibition on Cytochrome P450 1A1 and 1B1. Cancer Res. 2003, 63,
Jerina, D. M. Covalent Nucleoside Adducts of Benzo[a]pyrene 7,8- Diol 9,10-Epoxides: Structural Reinvestigation and Characterization (26) Picazo, A.; Salcedo, R. Carcinogenic Activity in Estrone and its of a Novel Adenosine Adduct on the Ribose Moiety. J. Org. Chem. Derivatives: a Theoretical Study. J. Mol. Struct. (THEOCHEM) 2003,
1991, 56, 20-29.
(5) Borosky, G. L. Theoretical Study Related to the Carcinogenic Activity (27) Tomasi, J.; Persico, M. Molecular Interactions in Solution: an of Polycyclic Aromatic Hydrocarbon Derivatives. J. Org. Chem. 1999,
Overview of Methods Based on Continuous Distributions of the Solvent. Chem. ReV. 1994, 94, 2027-2094.
(6) Barone, P. M. V. B.; Camilo, A., Jr.; Galva˜o, D. S. Theoretical (28) Floria´n, J.; Warshel, A. Langevin Dipoles Model for Ab Initio Approach to Identify Carcinogenic Activity of Polycyclic Aromatic Calculations of Chemical Processes in Solution: Parametrization and Hydrocarbons. Phys. ReV. Lett. 1996, 77, 1186-1189.
Application to Hydration Free Energies of Neutral and Ionic Solutes (7) Volk, D. E.; Rice, J. S.; Luxon, B. A.; Yeh, H. J. C.; Liang, C.; Xie, and Confomational Analysis in Aqueous Solution. J. Phys. Chem. B G.; Sayer, J. M.; Jerina, D. M.; Gorenstein, D. G. NMR Evidence for 1997, 101, 5583-5595.
Syn-Anti Interconversion of a Trans Opened (10R)-dA Adduct of (29) Floria´n, J.; Warshel, A. Calculations of Hydration Entropies of Benzo[a]pyrene (7S, 8R)-Diol (9R, 10S)-Epoxide in a DNA Duplex.
Hydrophobic, Polar, and Ionic Solutes in the Framework of the Biochemistry 2000, 39, 14040-14053.
Langevin Dipoles Solvation Model. J. Phys. Chem. B 1999, 103,
(8) Ponte´n, I.; Sayer, J. M.; Pilcher, A. S.; Yagi, H.; Kumar, S.; Jerina, D. M.; Dipple, A. Factors Determining Mutagenic Potential for (30) Schaftenaar, G. MOLDEN, Center for Molecular and Biomolecular Individual Cis and Trans Opened Benzo[c]phenanthrene Diol Epoxide- Informatics, University of Nijmegen, The Netherlands.
Deoxyadenosine Adducts. Biochemistry 2000, 39, 4136-4144.
(31) Baldridge, K. K.; Jonas, V. Implementation and Refinement of the (9) Wei, S.-J. C.; Chang, R. L.; Wong, C.-Q.; Bhachech, N.; Cui, X. X.; Modified Conductor-like Screening Quantum Mechanical Solvation Hennig, E.; Yagi, H.; Sayer, J. M.; Jerina, D. M.; Preston, B. D.; Model at the MP2 Level. J. Chem. Phys. 2000, 113, 7511-7518.
Conney, A. H. Dose-dependent Differences in the Profile of Mutations (32) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, Induced by an Ultimate Carcinogen from Benzo[a]pyrene. Proc. Natl. M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, Acad. Sci. U.S.A. 1991, 88, 11227-11230.
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, (10) Chlebowski, R. T.; Hendrix, S. L.; Langer, R. D.; Stefanick, M. L.; V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.
Gass, M.; Lane, D.; Rodabough, R. J.; Gilligan, M. A.; Cyr, M. G.; A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Thomson, C. A.; Khandekar, J.; Petrovitch, H.; McTiernan, A.; WHI Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, Investigators. Influence of Estrogen plus Progestin on Breast Cancer H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; and Mammography in Healthy Postmenopausal Women: the Women’s Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, Health Initiative Randomized Trial. JAMA 2003, 289, 3243-3253.
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P.
(11) Dalton, L. W. Weighing Risks of Estrogen Therapy. Chem. Eng. News Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; 2003, Oct. 6, 25-27.
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, (12) Beral, V. Million Women Study Collaborators. Breast Cancer and O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J.
Hormone-replacement Therapy in the Million Women Study. Lancet B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; 2003, 362, 419-427.
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; (13) Russo, J.; Hu, Y. F.; Tahin, Q.; Mihaila, D.; Slater, C.; Lareef, M.
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; H.; Russo, I. H. Carcinogenicity of Estrogens in Human Breast Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, Epithelial Cells. APMIS 2001, 109, 39-52.
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision (14) Cavalieri, E. L.; Stack, D. E.; Devanesan, P. D.; Todorovic, R.; B.03; Gaussian, Inc.: Pittsburgh, PA, 2003.
Dwivedy, I.; Higginbotham, S.; Johansson, S. L.; Patil, K. D.; Gross, (33) Floria´n, J.; Warshel, A. ChemSol, Version 1.1, University of Southern M. L.; Gooden, J. K.; Ramanathan, R., Cerny, R. L.; Rogan, E. G.
Molecular Origin of Cancer: Catechol Estrogen-3,4-quinones as (34) Floria´n, J.; Warshel, A. ChemSol, Version 2.1, University of Southern Endogenous Tumor Initiators. Proc. Natl. Acad. Sci. U.S.A. 1997, 94,
(35) Warshel, A. In Computer Modeling of Chemical Reactions in Enzymes (15) Stack, D. E.; Byun, J.; Gross, M. L.; Rogan, E. G.; Cavalieri, E. L.
and Solutions; John Wiley & Sons, Ed.; Wiley-Interscience: New Molecular Characteristics of Catechol Estrogen Quinones in Reactions with Deoxyribonucleosides. Chem. Res. Toxicol. 1996, 9, 851-859.
(36) Matsui, A.; Ikeda, T.; Enomoto, K.; Nakashima, H.; Omae, K.; (16) Li, K. M.; Todorovic, R.; Devanesan, P.; Higginbotham, S.; Kofeler, Watanabe, M.; Hibi, T.; Kitajima, M. Progression of Human Breast H.; Ramanathan, R.; Gross, M. L.; Rogan, E. G.; Cavalieri, E. L.
Cancers to the Metastatic State is Linked to Genotypes of Catechol- Metabolism and DNA Binding Studies of 4-hydroxyestradiol and O-methyltransferase. Cancer Lett. 2000, 150, 23-31.
314 J. Chem. Inf. Comput. Sci., Vol. 44, No. 2, 2004
(37) Dunning, A. M.; Healey, C. S.; Pharoah, P. D. P.; Teare, M. D.; Ponder, to Quinone Metabolites. J. Biol. Chem. 1994, 269, 284-291.
B. A. J.; Easton, D. F. A Systematic Review Of Genetic Polymor- (40) Rogan, E. G.; Badawi, A. F.; Devanesan, P. D.; Meza, J. L.; Edney, phisms and Breast Cancer Risk. Cancer Epidemiol., Biomarkers PreV. J. A.; West, W. W.; Higginbotham, S. M.; Cavalieri, E. L. Relative 1999, 8, 843-854.
Imbalances in Estrogen Metabolism and Conjugation in Breast Tissue (38) Yager, J. D.; Liehr, J. G. Molecular Mechanisms of Estrogen of Women with Carcinoma: Potential Biomarkers of Susceptibility Carcinogenesis. Annu. ReV. Pharmacol. Toxicol. 1996, 36, 203-232.
to Cancer. Carcinogenesis 2003, 24, 697-702.
(39) Wang, M. Y.; Liehr, J. G. Identification of Fatty Acid Hydroperoxide Cofactors in the Cytochrome P450-mediated Oxidation of Estrogens

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