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Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate.

Stack DE - Metabolites (2015)

Bottom Line: This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone.HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium.This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA. dstack@unomaha.edu.

ABSTRACT
Mechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE₁) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

No MeSH data available.


Oxidative metabolism of estrogen to catechol estrogens and estrogen o-quinones and subsequent reaction with DNA.
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metabolites-05-00475-f001: Oxidative metabolism of estrogen to catechol estrogens and estrogen o-quinones and subsequent reaction with DNA.

Mentions: An increased level of endogenous estrogens is linked to increased rates of breast, ovarian, endometrial and other cancers [1,2,3]. The metabolism of estrogen can produced reactive metabolites capable of binding to nucleophile sites in the DNA [4]. Estrone and β-estradiol are hydroxylated by various isoforms of cytochrome P-450 [5]. This A ring hydroxylation occurs mostly at the 2-position to produce 2-hydroxycatechol estrogens (2-OHE) (Figure 1). Certain P-450 enzymes, for example P-4501B1, hydroxylate primarily at the 4-position to produced 4-hydroxycatechol estrogens (4-OHE) [6]. These catechol estrogens can acts as procarcinogens since they are readily further oxidized to estrogen o-quinones (EQ) [7]. The two isomeric estrogen o-quinones, estrogen-2,3-quinone (E-2,3-Q) and estrogen-3,4-quinone (E-3,4-Q), are both strong electrophiles but they show significant differences with their reaction to DNA [8,9].


Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate.

Stack DE - Metabolites (2015)

Oxidative metabolism of estrogen to catechol estrogens and estrogen o-quinones and subsequent reaction with DNA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588807&req=5

metabolites-05-00475-f001: Oxidative metabolism of estrogen to catechol estrogens and estrogen o-quinones and subsequent reaction with DNA.
Mentions: An increased level of endogenous estrogens is linked to increased rates of breast, ovarian, endometrial and other cancers [1,2,3]. The metabolism of estrogen can produced reactive metabolites capable of binding to nucleophile sites in the DNA [4]. Estrone and β-estradiol are hydroxylated by various isoforms of cytochrome P-450 [5]. This A ring hydroxylation occurs mostly at the 2-position to produce 2-hydroxycatechol estrogens (2-OHE) (Figure 1). Certain P-450 enzymes, for example P-4501B1, hydroxylate primarily at the 4-position to produced 4-hydroxycatechol estrogens (4-OHE) [6]. These catechol estrogens can acts as procarcinogens since they are readily further oxidized to estrogen o-quinones (EQ) [7]. The two isomeric estrogen o-quinones, estrogen-2,3-quinone (E-2,3-Q) and estrogen-3,4-quinone (E-3,4-Q), are both strong electrophiles but they show significant differences with their reaction to DNA [8,9].

Bottom Line: This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone.HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium.This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA. dstack@unomaha.edu.

ABSTRACT
Mechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE₁) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

No MeSH data available.