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
C O N D U C T A S E N G A S T R O E N T E R O L O G Í A» Cáncer de Páncreas Autores: Nelson Condado, Iván Mosca � Clasificación • Tumores sólidos de páncreas exócrino: adenocarcinoma, carcinoma acinar y pancreatoblastoma • Tumores quísticos del páncreas exócrino: neoplasia mucinosa quística, neoplasia mucinosa papilar intraductal (TMPI*), neoplasia serosa qu�
UEFA EURO 2008TM La UEFA EURO 2008™ se llevará a cabo del 7 al 29 de junio de 2008 en Austria y Suiza. 16 equipos de toda Europa participarán para determinar, en el marco de 31 partidos, quien será el Campeón de Europa de Fútbol 2008. Los partidos se realizarán en las siguientes ocho ciudades: Viena, Innsbruck, Klagenfurt, Salzburgo, Berna, Basilea, Ginebra, Zurich . El torneo se