1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805 and
2 Department of Chemistry, Washington University, One Brookings Drive, St Louis, MO 63130, USA
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Abstract |
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Abbreviations: Ade, adenine; o-BQ, ortho-benzoquinone; CAT, catechol or 1,2-dihydroxybenzene; CE, catechol estrogen(s); CE-Q, catechol estrogen quinone(s); COMT, catechol-O-methyltransferase; DA, dopamine; dG, deoxyguanosine; DMF, dimethylformamide; E1, estrone; E2, estradiol; E1(E2)-3,4-Q, estrone(estradiol)-3,4-quinones or catechol estrogen-3,4-quinones; FAB, fast atom bombardment; Gua, guanine; MS/MS, tandem mass spectrometry; NADA, N-acetyldopamine; OHE1(E2), hydroxyestrone(estradiol); TFA, trifluoroacetic acid.
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Introduction |
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An important metabolic pathway of the estrogens, estrone (E1) and estradiol (E2), is formation of CE, namely, the hydroxylated estrogens, 4-hydroxyestrone(estradiol) (4-OHE1(E2)), which are carcinogenic in animals (9,10), and the isomeric 2-OHE1(E2). Oxidation of 4-OHE1(E2) to their quinones (E1(E2)-3,4-Q) and reaction with DNA form the 4-OHE1(E2)-1-N7guanine (Gua) and 4-OHE1(E2)-1-N3adenine (Ade) adducts by depurination (Figure 1) (4,5,11).
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Benzene
Benzene is carcinogenic and leukemogenic in rats and mice (1214), and epidemiological studies have established a relationship between exposure to benzene and acute myelogenous leukemia in humans (15,16). Several studies indicate that certain metabolites of benzene are responsible for both its cytotoxic and genotoxic effects (1720). High levels of peroxidase and a lack of quinone reductase in the bone marrow allow formation of toxic semiquinones and quinones without the possibility of their being reduced (21). Benzene is initially metabolized to phenol in the liver by cytochrome P450 2E1 (19,20,22,23). Other metabolites include catechol (CAT, 1,2-dihydroxybenzene), hydroquinone (1,4-dihydroxybenzene) and muconaldehyde (2426). Several studies have shown that CAT and hydroquinone accumulate in bone marrow (27,28), where they can be further activated to exert their myelotoxic effects (19). Oxidation of CAT and hydroquinone is catalyzed by peroxidases, including myeloperoxidase and prostaglandin H synthase (2935), and the resulting quinones can produce DNA adducts (3335).
We postulate that the leukemogenic effect of benzene may be mainly initiated by formation of CAT quinone and its reaction with DNA to form specific depurinating adducts.
Dopamine
The neurotransmitter DA is formed in the cell bodies of the dopaminergic neurons of the substantia nigra. Degeneration of the nigrostriatal dopaminergic neurons and decreased production of DA results in Parkinson's disease. The etiology of Parkinson's disease and its underlying mechanism of loss of DA neurons are unknown. There is evidence, however, that DA is involved in the etiology of this disease, based on the observation by Graham et al. (36) that DA is oxidized to the corresponding quinone. Injection of DA into neostriatum generates toxicity to dopaminergic neurons, and the toxicity correlates with protein binding (37,38). Glutathione and ascorbic acid (3739) diminish the toxicity of protein binding. Covalent binding of DA to DNA occurs upon incubating DA with HL-60 cells or human glioblastoma cell lines (40), by copper-mediated oxidation of DA (41) or by oxidation of DA with prostaglandin H synthase (42,43).
We hypothesize that oxidation of DA to its quinone and subsequent reaction with DNA cause DNA damage via formation of specific depurinating adducts, and the mutations generated by that damage may play a major role in initiating the series of events leading to neurodegenerative disorders such as Parkinson's disease. In general, catecholamine neurotransmitters such as DA can produce semiquinones and quinones via autoxidation, metal ion oxidation, and peroxidative enzyme or cytochrome P450 oxidation (44,45). This oxidative process is similar to the one described above for the benzene metabolite CAT and for the 4-OHE1(E2) formed by the metabolism of E1 and E2 (4,5).
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Materials and methods |
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Instrumentation
UV.
The UV spectra were obtained during HPLC by using the photodiode array detector (Waters 996, Milford, MA) for all compounds synthesized. HPLC separations were monitored at 280 nm.
NMR.
Proton and homonuclear two-dimensional chemical shift correlation spectroscopy NMR spectra were recorded in DMSO-d6 with one drop of D2O and one drop of CD3COOD on a Varian Unity 500 instrument at 499.835 MHz at 25°C. Chemical shifts are reported relative to DMSO (2.5 p.p.m.).
Mass spectrometry.
Exact mass measurements of fast atom bombardment (FAB)-produced ions were carried out on a Kratos MS-50 double focusing mass spectrometer in a peak-match mode. Confirmation of the presence of each adduct was by capillary HPLC coupled via electrospray ionization with a Finnigan LCQ ion trap mass spectrometer operating in the tandem mass spectrometry (MS/MS) mode. The HPLC (Microtech Scientific) made use of a binary gradient of solvent A (0.5% CH3COOH (v/v) in H2O) and solvent B (0.5% CH3COOH (v/v) in CH3OH) at a flow rate of 40 µl/min with a split of 10:1. The column was 0.3 x 100 Zorbax C18 (Microtech Scientific) with a flow rate on the column of 4 µl/min. The gradient was 95%A/5%B initially for 4 min, then linearly adjusted to 60/40 over 14 min, and held at 60/40 for 20 min.
HPLC methods for synthetic standards.
HPLC was conducted on a Waters (Milford, MA) 600 E system equipped with a Waters 996 photodiode array detector interfaced with an NEC-Powermate computer. Analyses and preparative separations were carried out on reverse-phase C-18, YMC (Morris Plains, NJ) columns (5 µm, 120, ODS-AQ (6 x 250 mm) and ODS-AQ, 5 µm, 120
, (20 x 250 mm), respectively) using specific mobile phases for the different compounds.
Synthesis of standard adducts
Catechol adducts.
Because the ortho-benzoquinone (o-BQ, nascent quinone) is rather unstable, various methods of synthesis were tested to obtain its maximum yield. Oxidation of CAT using Ag2O in dry dimethylformamide (DMF) was the best method. A solution of CAT (100 mg, 0.91 mmol) in dry DMF (7.5 ml) was stirred with Ag2O (842 mg, 3.60 mmol) for 30 min at 0°C. The extent of formation of o-BQ was followed by HPLC, using a linear analytical gradient from 100% H2O (0.01% TFA, pH 2.6) to 30% CH3CN in 60 min at a flow rate of 1 ml/min (monitored by UV absorbance at 300 nm on a Waters 996 photodiode array detector). The yield of o-BQ was >95%.
The dark red solution was immediately filtered into a solution of dG (1.20 g, 4.54 mmol) or Ade (613 mg, 4.54 mmol) in DMF/CH3COOH/H2O, 7.5 ml each (Figure 2). The reaction mixture was stirred for 8 h at room temperature, filtered and washed with 10 ml of DMF/CH3COOH/H2O (2:1:1). The reddish-brown filtrate was directly subjected to HPLC purification, using a linear preparative gradient of 20% CH3CN in H2O (0.01% TFA) to 80% CH3CN in H2O (0.01% TFA) over 60 min at a flow rate of 9 ml/min with dG or 15% CH3CN in H2O (0.01% TFA) to 60% CH3CN in H2O (0.01% TFA) over 60 min at a flow rate of 9 ml/min with Ade. The products, isolated under an argon atmosphere and stored at 20° C in 2 ml of DMF/CH3COOH/H2O (2:1:1), were CAT-4-N7Gua and CAT-4-N3Ade, the result of a 1,4-Michael addition between dG or Ade and o-BQ.
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For CAT-4-N3Ade, the yield was 65%; UV: max, 279 nm. 1H NMR,
(p.p.m.): 6.95 (bd, 2H, 5-H, 6-H), 7.08 (s, 1H, 3-H), 8.52 (s, 1H, 2-H (Ade)), 8.76 (s, 1H, 8-H (Ade)). FAB MS, (M + H)+, C11H9N5O2: calcd m/z 244.0836; obsd m/z 244.0834.
N-Acetyldopamine adducts.
A solution of NADA (9 mg, 0.047 mmol) in 1.5 ml of CH3COOH/ H2O (1:1) was stirred with NaIO4 (5 mg, 0.023 mmol) for 5 min at room temperature. To the resulting red solution of the NADA quinone was added 5 equivalents of dG (59 mg, 0.23 mmol) in 1.5 ml of CH3COOH/H2O (1:1) (Figure 3). The reaction mixture was stirred for 3 h at room temperature and then separated by HPLC, using a 45 min linear preparative gradient from 10% CH3CN in H2O (0.01% TFA) to 30% CH3CN in H2O (0.01% TFA) at a flow rate of 10 ml/min. The yield of NADA-6-N7Gua was 58%.
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To synthesize the Ade adduct, a solution of NADA (20 mg, 0.094 mmol) in 2 ml of CH3COOH/H2O (1:1) was oxidized with NaIO4 (10 mg, 0.047 mmol) and reacted with Ade (63 mg, 0.47 mmol), as described above for the reaction with dG. The product, NADA-6-N3Ade, was purified by HPLC, using a preparative linear gradient from 5% CH3CN in H2O (0.01% TFA) over 60 min to 40% CH3CN in H2O (0.01% TFA) at a flow rate of 9 ml/min. The yield was 51%; UV: max, 275 nm. 1H NMR (p.p.m.): 1.90 (s, 3H, CH3), 2.152.30 (m, 2H, 7-CH2), 2.833.10 (m, 2H, 8-CH2), 6.81 (s, 1H, 5-H), 6.85 (s, 1H, 2-H), 8.45 (s, 1H, 2-H (Ade)), 8.65 (s, 1H, 8-H (Ade)). FAB MS, (M + H)+, C15H17N6O3: calcd m/z 329.1361; obsd m/z 329.1362.
Dopamine adducts.
DA-HCl (50 mg, 0.264 mmol) and dG (622 mg, 2.6 mmol) were dissolved in 13 ml of CH3COOH/H2O (1:1). To this mixture a solution of NaIO4 (28 mg, 0.13 mmol) in 2 ml of CH3COOH/H2O (1:1) was added dropwise over 10 min (Figure 3). After 3 h at room temperature, the reaction was terminated, and the product, DA-6-N7Gua, was purified by preparative HPLC, using a linear gradient from 10% CH3CN in H2O (0.01% TFA) to 30% CH3CN in H2O (0.01% TFA) over 60 min, then to 80% CH3CN in 15 min at a flow rate of 8 ml/min. The colorless semi-solid product was obtained in 46% yield. UV:
max, 245 (sh), 283 nm. 1H NMR (p.p.m.): 2.45 (m, 2H, 7-CH2), 2.75 (m, 2H, 8-CH2), 6.70 (s, 1H, 5-H), 6.76 (s, 1H, 2-H), 8.15 (s, 1H, 8-H (Gua)). FAB MS, (M + H)+, C13H14N6O3: calcd m/z 303.1207; obsd m/z 303.1205.
A solution of DA-HCl (50 mg, 0.26 mmol) and Ade (356 mg, 2.64 mmol) in 13 ml of CH3COOH/H2O (1:1) was treated with a solution of NaIO4 (28 mg, 0.13 mmol) in 2 ml of CH3COOH/H2O (1:1) in a manner similar to that used to synthesize DA-6-N7Gua. After 3 h at room temperature, the reaction was terminated. The mixture was subjected to preparative HPLC, using H2O (0.01% TFA) at a flow rate of 5 ml/min for 20 min, followed by a linear gradient to 80% CH3CN in H2O (0.01% TFA) over 40 min at a flow rate of 10 ml/min. DA-6-N3Ade was obtained in 40% yield. UV: max, 279 nm. 1H NMR (p.p.m.): 2.40 (m, 2H, 7-CH2), 2.82 (m, 2H, 8-CH2), 6.80 (s, 1H, 5-H), 6.86 (s, 1H, 2-H), 8.05 (s, 1H, 2-H (Ade)), 8.40 (s, 1H, 8-H (Ade)). FAB MS, (M + H)+, C13H14N6O2: calcd m/z 287.1258; obsd m/z 287.1256.
Enzymatically-catalyzed covalent binding of catechol and dopamine to DNA
CAT and DA were bound to DNA in 10 ml reaction mixtures containing 3 mM calf thymus DNA in 0.067 M sodium-potassium phosphate (pH 7.0), 0.8 µM CAT or DA in 50 µl DMSO and 1 mg horseradish peroxidase plus 0.5 mM H2O2 or 1 mg mushroom tyrosinase. CAT and DA (0.8 µM) were also activated by 10 mg of phenobarbital-induced rat liver microsomes (46) in 150 mM TrisHCl (pH 7.5), 150 mM KCl, 5 mM MgCl2, 1 mM cumene hydroperoxide and 3 mM DNA. The reactions were incubated for 2 h at 37°C. A 1-ml aliquot was used for analysis of stable DNA adducts by the 32P-postlabeling method with 8 µg of DNA (47). The DNA was precipitated from the remaining reaction mixture with two volumes of ethanol, and the supernatant was used for structure determination of depurinating adducts. After evaporation under vacuum, the residue was dissolved in 1 ml of DMSO/CH3OH. The CAT adducts were first separated by HPLC on a preparative column with a curvilinear gradient (CV 6) from 100% H2O (0.01% TFA) to 15% CH3OH in H2O (0.01% TFA) in 60 min at a flow rate of 3 ml/min. Fractions at the retention times of CAT-4-N3Ade (34.5 min) and CAT-4-N7Gua (40 min) were collected and analyzed by HPLC, which was eluted with aqueous 50 mM (NH4)3PO4, 5 mM sodium dodecyl sulfate, 1% CH3COOH at a flow rate of 0.5 ml/min. The DA adducts were first separated by HPLC on a preparative column eluted with a curvilinear gradient (CV 6) from 100% aqueous 50 mM (NH4)3PO4, 5 mM sodium dodecyl sulfate, 4% CH3COOH to 100% CH3CN at a flow rate of 0.5 ml/min. Fractions were collected at 34 min for DA-6-N3Ade and 37 min for DA-6-N7Gua and analyzed by HPLC as described above for the CAT adducts. The remainder of the collected fractions was used to confirm the structures of the adducts by MS.
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Results |
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Structure elucidation of adducts
Catechol adducts.
The reaction of o-BQ with the deoxyribonucleoside bases to afford the desired adducts is an acid-assisted 1,4-Michael addition reaction analogous to that of CE quinones with nucleobases (48,49). With o-BQ, however, the reaction in CH3COOH/H2O (1:1) did not yield any products, due to the instability of o-BQ. To render this reaction feasible a compromise was reached by conducting it in DMF/CH3COOH/H2O (2:1:1).
Reaction of o-BQ with dG afforded CAT-4-N7Gua (Figure 2). The structure was readily determined by both NMR and MS analysis. By MS, the (M + H)+ ion had an m/z 260, indicating that deoxyribose had been lost. This implies that Gua is bonded to CAT at the N-7. The NMR resonance of the 5-H and 6-H of the CAT moiety as a singlet at 6.79 p.p.m. and the 3-H as a singlet at 7.08 p.p.m. indicates that the bond to Gua in the CAT aromatic ring occurs at C-4.
For CAT-4-N3Ade, the structure was consistent with the NMR spectrum, showing the aromatic protons 5-H and 6-H as a doublet at 6.95 p.p.m., and the singlet at 7.08 p.p.m. that was assigned as 3-H. Furthermore, the 2-H and 8-H of the Ade moiety were observed at 8.52 and 8.76 p.p.m., respectively. The mass of the FAB-produced ion at m/z 244 corroborated the structure of this adduct.
Under the same conditions, o-BQ adducts of deoxyadenosine, deoxycytidine and thymidine were not obtained. Furthermore, reaction of the stable 1,4-benzoquinone (p-BQ) with dG, Ade, deoxyadenosine, deoxycytidine or thymidine did not afford any detectable adducts.
Dopamine adducts.
The oxidation of DA and subsequent reaction with dG or Ade were more difficult to accomplish because the amino group of the DA quinone reacts intramolecularly by a 1,4-Michael addition to produce a dihydroindole, a precursor to neuromelanin biosynthesis. This reaction competes with the intermolecular acid-assisted 1,4-Michael addition of the nucleophilic groups of dG and Ade to the DA quinone. To avoid the competitive cyclization reaction, NADA, in which the nucleophilic amino group of DA is acetylated, was oxidized to its quinone and reacted with deoxyribonucleosides or nucleobases.
N-Acetyldopamine: The structure of the NADA-6-N7Gua adduct (Figure 3) was consistent with MS results, which showed an m/z 345 ion, indicating the loss of the deoxyribose moiety. It was also consistent with the NMR results: the two aromatic protons of the NADA moiety, 5-H and 2-H, resonate at 6.62 and 6.70 p.p.m., respectively, assuming that the reaction was a 1,4-Michael addition. If the reaction occurred by 1,6-addition, however, we should have obtained an adduct at C-2 and/or C-5 of NADA. Reaction at C-2 can be disregarded on the basis that the aromatic protons did not resonate as doublets. The adduct with the Gua-NADA bond at C-5, formed by 1,6-addition, was eliminated from consideration by a nuclear Overhauser enhancement experiment in which the resonance of the 7-CH2 protons at 2.25 p.p.m. was irradiated. This structure would entail that both the resonance signals corresponding to 2-H and 6-H be enhanced. In fact, only the signals corresponding to the 2-H of NADA at 6.70 p.p.m. and the 8-H of the Gua moiety at 7.85 p.p.m. were enhanced. This result unequivocally assigns the structure of the adduct as NADA-6-N7Gua, proving that the reaction is a 1,4-Michael addition. Following the same approach, the structure of NADA-6-N3Ade was assigned.
Dopamine.
Reactions of DA-HCl were set at pH 1.2 in CH3COOH/H2O (1:1) to minimize intramolecular 1,4-Michael addition of DA and favor intermolecular 1,4-Michael addition of dG or Ade to the 6 position of DA quinone. Although cyclization was avoided under these conditions, owing to the extensive protonation of the DA amino group, minor side reactions such as dimerization and subsequent oligomerization of the resulting DA quinone could not be eliminated. To minimize these competing reactions and obtain the best yields, we generated the DA o-quinone in situ by adding a solution of NaIO4 to a mixture of DA-HCl and dG or Ade.
The structures of the adducts obtained by reaction of DA quinone with dG or Ade, DA-6-N7Gua and DA-6-N3Ade (Figure 3), were elucidated following the same criteria adopted for the NADA adducts. Under the above conditions, DA quinone did not react with deoxyadenosine, deoxycytidine or thymidine to form adducts to any measurable extent.
In conclusion, the reaction of CAT quinone and DA quinone with dG or Ade involves the specific nucleophilic sites of the N-7 of Gua and N-3 of Ade in the 1,4-Michael addition. The reactions of E1(E2)-3,4-Q with dG or Ade by 1,4-Michael addition exhibit the same specificity, forming N7Gua and N3Ade depurinating adducts (11,48).
Enzymatically-catalyzed covalent binding of catechol and dopamine to DNA
Conversion of CAT and DA to their quinones can generally occur by autoxidation, metal-ion oxidation or cytochrome P450 or peroxidase-catalyzed oxidation (44,45). In vivo the copper-containing enzyme tyrosinase oxidizes DA to its quinone. To demonstrate binding to DNA in vitro, CAT and DA were oxidized in reactions catalyzed by horseradish peroxidase, tyrosinase or phenobarbital-induced rat liver microsomes in the presence of DNA (Table I). All three enzymes catalyzed formation of detectable amounts of the depurinating adducts of DA, DA-6-N3Ade and DA-6-N7Gua, as well as the CAT-4-N7Gua depurinating adduct of CAT. In contrast, the CAT-4-N3Ade adduct was detected only after activation by tyrosinase.
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Confirmation of the presence of each depurinating adduct reported in Table I was by capillary HPLC/tandem mass spectrometry. We required that the unknowns have identical HPLC retention times as the standards and give product-ion spectra of the (M + H)+ ions containing the same two or three intense signals as those of the standards. The product-ion spectrum of the two modified guanine (M + H)+ ions showed that losses of 17 (NH3) and 42 (NC-NH2) occurred for both. The CAT-modified Gua showed an additional loss of 24 (possible via formation of an ion-molecule product in the trap), whereas the DA-modified Gua underwent a loss of 35 (NH3 and H2O). The modified bases isolated from the in vitro experiments showed these same ions. The (M + H)+ ions of the adenines modified with CAT or DA fragmented by losses of 17 and 46, and the unknowns also showed signals for these processes. The product-ion spectra of all the in vitro adducts showed other comparable or weaker signals owing to coeluting interferences from the reaction mixture.
In summary, enzymatic oxidation of CAT or DA in the presence of DNA resulted in the formation of 9499.9% depurinating CAT adducts or 9599% depurinating DA adducts.
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Discussion |
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The role of estrogens in causing DNA damage (4,5,50) is better understood than that of CAT and DA. The estrogens E1 and E2, which are biochemically interconvertible, are metabolized via two major pathways: formation of CE and, to a lesser extent, 16-hydroxylation. In general, estrogens and CE are inactivated by conjugating reactions, such as glucuronidation and sulfation, especially in the liver. The most common pathway of CE conjugation in extrahepatic tissues is O-methylation catalyzed by the ubiquitous catechol-O-methyltransferase (COMT, Figure 1
). Relatively high levels of cytochrome P450 1B1 and other 4-hydroxylases could cause the 4-OHE1(E2), which are usually minor metabolites, to be the major ones, rendering conjugation of 4-OHE1(E2) via methylation in extrahepatic tissues insufficient. In this case, competitive catalytic oxidation of CE to CE quinones could occur (Figure 1
). Redox cycling generated by reduction of CE-Q to CE semiquinones, catalyzed by cytochrome P450 reductase, and subsequent oxidation back to CE-Q by molecular oxygen causes formation of superoxide anion radicals and, subsequently, hydroxyl radicals (not shown in Figure 1
) (1). This process, which also occurs with the quinones of CAT and DA, may constitute a significant source of reactive oxygen species. Hydroxyl radicals can also react with DNA and contribute to total DNA damage.
CE-Q can be inactivated by conjugation with glutathione (Figure 1). A second inactivating pathway for CE-Q is their reduction to CE by quinone reductase and/or cytochrome P450 reductase (Figure 1
) (51,52). If the two inactivating processes are insufficient, CE-Q may react with DNA to form predominantly stable adducts for the 2-OHE1(E2) (not shown in Figure 1
) (4,48,53) and predominantly depurinating adducts for the 4-OHE1(E2) (Figure 1
) (4,11,48). The depurinating adducts generate apurinic sites that may lead to oncogenic mutations (68), thereby initiating a variety of human cancers, including breast and prostate. In support of this hypothesis, a burst of apurinic sites leads to mutations in the H-ras gene of mouse skin treated with E2-3,4-Q (8).
The initiating mechanism of carcinogenesis for the synthetic estrogen hexestrol may have a similar explanation. This compound, which is carcinogenic in the kidney of Syrian golden hamsters (54,55), also has catechol as a major metabolite (55,56), which can be metabolically converted to catechol quinone. The catechol quinone of hexestrol has chemical properties similar to those of E1(E2)-3,4-Q, namely, it specifically forms an N7Gua adduct by 1,4-Michael addition after reaction with dG or DNA (49).
The formation of depurinating adducts specifically at the N-7 of Gua and N-3 of Ade by 1,4-Michael addition to CAT quinone, analogously to those formed by E1(E2)-3,4-Q, leads us to hypothesize that the metabolite CAT may play a major role in tumor initiation by benzene. In fact, CAT is carcinogenic in mice and rats, inducing glandular stomach tumors in these animals (57). The overall leukemogenicity of benzene could result from a synergistic genotoxic response to CAT quinone, which predominantly produces depurinating DNA adducts, and 1,4-benzoquinone, which produces only stable DNA adducts (33,34,58,59).
One of the functions of the neurotransmitter DA or its precursor, L-Dopa, is the synthesis of neuromelanin (60). This occurs by oxidation of DA to its o-quinone, followed by intramolecular cyclization of the nucleophilic amino group via a 1,4-Michael addition (Figure 4). The product, leucochrome, is further oxidized to aminochrome, which, after tautomerization to its quinone methide and quinone imine, polymerizes to neuromelanin, the pigment of the substantia nigra. Disregulation of DA compartmentalization may lead to DA quinone formation by various oxidants (4245). Under these circumstances, intermolecular 1,4-Michael addition of the N-7 of Gua or N-3 of Ade in DNA to DA quinone could compete successfully with the intramolecular cyclization of DA quinone that leads to dihydroindole derivatives (Figure 4
). In fact, DA cyclizes at a slower rate than L-Dopa and epinephrine (61). Thus, if oxidation of DA to its quinone does not occur in a properly controlled environment, we hypothesize that the quinone might react with DNA to form depurinating DNA adducts, generating mutations that could initiate neurodegenerative disorders such as Parkinson's disease.
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Summary |
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Notes |
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* The term catechol refers to an aromatic ring with vicinal hydroxyl substituents. In this article catechol is spelled out when it is used in a general sense. When it refers specifically to the compound 1,2-dihydroxybenzene, normally called catechol, it is abbreviated CAT.
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Acknowledgments |
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References |
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