* VA Medical Center, Division of Geriatric Medicine and Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri; and
Department of Medicine, Washington University, St. Louis, Missouri
Received March 3, 1999; accepted October 19, 1999
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ABSTRACT |
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Key Words: hypochlorous acid; aromatic amines; DNA adducts; N-acetylbenzidine; benzidine..
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INTRODUCTION |
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HOCl is microbicidal and induces oxidative injury during phagocytosis. When exposed to bacteria, HOCl kills cells within seconds via mechanisms involving ATP depletion and inhibition of membrane transporters and respiratory enzymes (Albrich et al., 1981; Barrette et al., 1989
). With mammalian cells, HOCl can oxidize many important biologic constituents such as proteins, fatty acids, cholesterol, and DNA. Reactions demonstrated include conversion of primary and secondary amines to both mono- and di-N-chloramines (Thomas et al., 1986
), oxidation of free amino groups to aldehydes (Hazen et al., 1998
), and chlorination of fatty acids and cholesterol (Hazen et al., 1996
; Carr et al., 1996
). These modifications have been implicated in the pathogenesis of conditions ranging from aging to atherosclerosis (Berlett and Stadtman, 1997
; Steinberg, 1997
). Although treatment of DNA with HOCl causes large increases in pyrimidine oxidation (i.e., thymine glycols), purine oxidation (8-hydroxyguanine) was not detected (Whiteman et al., 1997
). HOCl oxidizes a variety of aromatic amines to dications or nitrenium ions that react with DNA forming adducts (Kozumbo et al., 1992
; Uetrecht et al., 1995
; Liu and Uetrecht, 1995
; Ritter and Malejka-Giganti, 1989
).
Animal and epidemiologic studies indicate that urinary tract infection is a significant risk factor for the development of bladder cancer. Using the heterotopically transplanted rat urinary bladder, heat-killed Escherichia coli or its endotoxin lipopolysaccharide increased the number of tumors in rats receiving a single dose of N-methyl-N-nitrosourea (Yamamoto et al., 1992). In this model, migration of polymorphonuclear leukocytes into the urothelium and of other inflammatory cells into the lamina propria was observed (Kawai et al., 1993
; Yamamoto et al., 1992
). A close association has been reported for chronic urinary tract infections and vulnerability to bladder cancer in patients who are paraplegic secondary to spinal cord injury (Bejany et al., 1987
) and individuals who are infected with Schistosomal haematobium (El-Sebai, 1981
). Smoking was found to significantly increase the odds ratio for bladder cancer in individuals with a history of Schistosomal haematobium infections (Bedwani, 1998
).
Aromatic amines are prevalent in cigarette smoke (Patrianakos and Hoffmann, 1979) and are thought to contribute to a 2- to 3-fold increase in the relative risk of developing bladder cancer (Ross et al., 1988
). 4-Aminobiphenyl is an aromatic amine constituent of cigarette smoke (Patrianakos and Hoffmann, 1979
). Relationships have been established between both 4-aminobiphenyl-hemoglobin and 4-aminobiphenyl-DNA adduct levels in urothelial cells and the occurrence of bladder cancer, suggesting a causal role for tobacco smoking (Bartsch et al., 1993
). Peripheral white blood cells or their polymorphonuclear leukocyte, monocyte, and lymphocyte subpopulations are used as surrogate tissue to assess environmental exposure and have demonstrated increased levels of 4-aminobiphenyl-DNA adduct in smokers compared to nonsmokers (Dallinga et al., 1998
).
Peripheral white blood cells (Zhou et al., 1997) and exfoliated urothelial cells (Rothman et al., 1996
) from workers exposed to benzidine contain the same major DNA adduct. Levels of adduct in peripheral white blood cells correlated with levels in exfoliated bladder cells. This adduct N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ) is mutagenic and thought to be responsible for the initiation of bladder carcinogenesis by benzidine (Beland et al., 1983
; Fox et al., 1990
; Heflich et al., 1986
; Melchior, Jr. et al., 1994
). N-Acetylbenzidine (ABZ) is the major metabolite observed in urine (Hsu et al., 1996
) and plasma of workers exposed to benzidine. Therefore, this N-acetylated arylamine is the likely substrate involved in adduct formation. ABZ activation by white blood cells may contribute to the formation of dGp-ABZ in these cells and bladder cells. This study is designed to assess the formation and characterization of dGp-ABZ derived from the reaction of HOCl with ABZ. Results from this study are expected to provide insight into the possible metabolism and activation of ABZ by neutrophile/monocyte-derived HOCl to form dGp-ABZ. An easy, convenient method is described for preparing dGp-ABZ, and other 2'-deoxyguanosine analogues for use as standards in qualitative and quantitative assessment of adduct levels.
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MATERIALS AND METHODS |
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Reaction of ABZ with HOCl.
3H-ABZ (0.06 mM) was added to 100 mM phosphate buffer pH 5.5 or 7.4, containing 0.1 mM DETAPAC in a total volume of 0.1 ml. The reaction was started by the addition of NaOCl to a final concentration of 0.1 mM and incubated at 37°C for 1 min. A 1 mM stock solution of NaOCl was made in 0.025 N NaOH. Where indicated, 1 mg/ml DNA or 3 mg/ml nucleosides/nucleotides were present at the beginning of the incubation. Similar results were observed in the presence or absence of DETAPAC. Blank values were obtained in the absence of NaOCl. The reaction was stopped by adding 0.01 ml of 10 mM methionine, 0.2 ml of dimethylformamide, and frozen. Transformation was assessed by HPLC as described below. Samples containing DNA or dGp were extracted twice with two volumes of ethyl acetate, and the aqueous fraction was processed as described below.
HPLC analysis of products.
Products were assessed using a Beckman HPLC with System Gold software, which consisted of a 5-µm, 4.6 x 150 mm C-18 ultrasphere column attached to a guard column. For solvent system 1, the mobile phase contained 20 mM phosphate buffer (pH 5.0) in 50% methanol, 02 min; 5060%, 27 min; 6090%, 727 min; 9050%, 3540 min; flow rate 1 ml/min. For solvent system 2, the mobile phase contained 20 mM phosphate buffer (pH 5.0) in 20% methanol, 02 min; 2033%, 28 min; 3340%, 815 min; 4080%, 1522 min; 8020%, 3237 min; flow rate 1 ml/min. Radioactivity in HPLC eluents was measured using a FLO-ONE radioactive flow detector. Data are expressed as a % of total radioactivity recovered by HPLC. The amount of ABZ transformed was determined by subtracting the % of ABZ recovered (unchanged) from 100%. Some fractions were also collected for 32P-postlabeling.
Preparation of DNA adduct.
DNA was prepared as previously described (Lakshmi et al., 1998). Following treatment with proteinase K and ribonuclease A and T1, the purity of DNA was evaluated by the ratio of A260/A280 to be approximately 1.7 for each sample. DNA samples were enzymatically hydrolyzed to dGp adducts by digestion with micrococcal nuclease and spleen phosphodiesterase (Gupta et al., 1982
). Enrichment of the adduct from unmodified nucleotides was achieved with n-butanol extraction (Gupta, 1985
). After ethyl acetate extraction, tetrabutylammonium chloride (1 mM) was added to the aqueous fraction along with an equal volume of n-butanol. Following three extractions, the n-butanol layers were pooled, back-extracted with water twice, evaporated using a speed vac, and dissolved in 0.05 ml distilled water.
Nuclease P1 hydrolysis of dGp adduct.
The enriched adduct sample was added to a reaction mixture containing 0.1 M sodium phosphate, pH 5.5, and 0.15 mM ZnCl2 at 37°C (Reddy and Randerath, 1986). One aliquot was incubated with 2 µg nuclease P1, while another aliquot was incubated without nuclease for the indicated time. Sensitivity is indicated by cleavage of the 3'-phosphate of dGp-ABZ to dG-ABZ. Samples were analyzed by HPLC using solvent system 2.
Adduct analysis by 32P postlabeling.
The dGp adduct was analyzed by 32P-postlabeling as previously described (Gupta et al., 1982; Lakshmi et al., 1995
). Labeled adduct was separated on PEI-cellulose sheets using the following multicomponent solvent systems: D-1 = 1.7 M sodium phosphate (pH 5.5); D-3 = 4 M ammonium hydroxide; D-4 = 0.6 M lithium formate/0.5 M TrisHCl/7 M urea (pH 8.0). 32P-labeled adduct was observed by autoradiography. The adduct was extracted from plates with 14 M ammonium hydroxide:methanol (1:1), evaporated, redissolved in methanol, and further analyzed by HPLC using solvent system 2 described above. In addition to synthetic dGp-ABZ (Lakshmi et al., 1995
), an identical standard was prepared by the incubation of N'-hydroxy-N-acetylbenzidine with either calf thymus DNA or dGp (Lakshmi et al., 1998
).
Preparation of dG-ABZ and dGp-ABZ for NMR and MS analysis.
To prepare a sufficient amount of dG-ABZ adduct for NMR analysis, the ratio of HOCl to ABZ was kept constant while the concentration of ABZ and HOCl was increased to 0.24 and 0.4 mM, respectively, at pH 5.5. Following a 10-ml incubation with 3 mg/ml dG, the HOCl/ABZ reaction mixture was applied to a 500-mg C-18 Bakerbond spe column. After washing with water (20 ml), the adduct was eluted with 4 ml of 100% methanol. The adduct was further purified with the HPLC system described above using a mobile phase consisting of 20 mM phosphate buffer (pH 5.0) in 35% methanol, 02 min; 3541%, 28 min; 4180%, 814 min; 8035%, 1925 min; flow rate 1 ml/min. With this solvent system, the elution times of ABZ and dG-ABZ were 10.2 and 15.9 min, respectively.
Following a 10-ml incubation with 3 mg/ml dGp, the reaction mixture was extracted four times with three volumes of ethyl acetate. dGp-ABZ was recovered by adding an equal volume of n-butanol and extracting three times. The pooled n-butanol extracts were further purified by HPLC using solvent system 2 and then 1.
Mass spectral analysis.
Electrospray ionization mass spectrometry (ESI/MS) analyses were performed on a Finnigan (San Jose, CA) TSQ-7000 triple-stage quadrupole spectrometer equipped with a Finnigan ESI source and controlled by Finnigan ICIS software operated on a DEC alpha workstation. Samples were loop injected onto the ESI source with a Harvard syringe pump at a flow rate of 5 µl/min. The electrospray needle and the skimmer were at ground potential and the electrospray chamber and the entrance of the glass capillary were at 4.4 kV. The heated capillary temperature was 200°C. For collisionally activated dissociation (CAD) tandem mass spectra, the collision gas was argon (2.22.5 mtorr), and collision energy was set at 50 eV. Product ion spectra were acquired in the profile mode at the scan rate of one scan per 3 sec.
NMR analysis.
Samples were prepared in 100% d6-DMSO (Aldrich gold label) under dry nitrogen purge. About 30 µg of the sample was dissolved in 1 ml of DMSO and transferred into high quality 5-mm tubes and capped under nitrogen. NMR spectra were acquired on a Varian Inova-500 instrument with proton resonance frequency at 499.97 MHz with an INVERSE probe (1H 90 pulse of 9 microsec). 128 transients were signal averaged with a recycle delay of 5 s and a 45-degree tip. The time domain data was processed on a SUN work station using the VNMR software. A line broadening parameter of 0.5 Hz was used for the Fourier transformation. Chemical shifts were referenced to TMS at 0.0 ppm.
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RESULTS |
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To better understand the ABZ and HOCl reaction, the concentration of 3H-ABZ was kept constant at 0.06 mM and the concentration of HOCl was varied from 0.025 to 0.2 mM (Fig. 1). From 0.025 to 0.1 mM HOCl, a rather linear increase in ABZ transformation and product formation was observed (Fig. 1
, panel A). At 0.1 mM HOCl, less than 20% of ABZ remains unchanged. Because 80% of ABZ was already transformed with 0.1 mM HOCl, little additional transformation and product formation was observed when the concentration of HOCl was increased to 0.2 mM. The amount of ABZ transformed per nanomole of HOCl present was relatively constant from 2.5 to 10 nmoles of HOCl (Fig. 1
, panel B). Over this linear range of transformation, the average ratio of oxidant HOCl to reductant ABZ transformed was about 2. Similar results were observed at pH 7.4.
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DISCUSSION |
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Although examination of the mechanism of ABZ activation is beyond the focus of this study, information gathered from this and other studies can address this issue. Horseradish peroxidase and prostaglandin H synthase peroxidatically metabolize benzidine to a radical cation and then a diimine (Josephy et al., 1983; Wise et al., 1985
). Although HOCl oxidation of ABZ may be by electron withdrawal, spectral studies have not indicated the presence of a diimine (not shown). Oxidation of ABZ may result in the formation of a less ring-activated intermediate, such as a diimine monocation, which is a resonance structure of the ABZ nitrenium ion. This intermediate has been proposed recently as the reactive intermediate responsible for dGp-ABZ formation (Dicks et al., 1999
). Alternatively, HOCl reacts with amines to form chloramines (Thomas et al., 1986
), which could lose HCl, forming a diimine or imidoimine. However, HOCl oxidation of 4-aminobiphenyl does not result in formation of an N-chloro intermediate (Scarborough and Waters, 1926
). Ongoing experiments are directed at identification of labile reaction products, which will assist in assessing the mechanism of ABZ activation to form dGp-ABZ.
Both pH 5.5 and 7.4 were selected to assess transformation, because the pH involved in HOCl's possible carcinogenic effect is not known. Whereas the pH inside a phagosome can be quite acidic, other parts of the cell exhibit a more neutral pH, and HOCl released from cells would be exposed to a varied environment. The major pH effect observed was the reaction of activated ABZ with 2'-deoxyguanosine 3'- and 5'-monophosphates (Table 2). A higher rate of adduct formation was observed with the former at the acidic pH, whereas the latter exhibited a higher rate at the neutral pH. Previous studies with aromatic amines have demonstrated a higher rate of adduct formation at acidic pH and attributed this to stabilization of a nitrenium ion or increased electrophilicity of a iminoquinone due to protonation of the imine nitrogen (Yamazoe et al., 1985
). This does not seem likely in the present case because neither intermediate has been detected and these intermediates would not be expected to be more reactive with dpG at pH 7.4 than 5.5. However, although the general overall charge may be similar for both nucleotides at each pH, their relative conformations may be different and that may alter their reactivity. The 7.46 pKa for HOCl may also contribute to the pH effect observed in Table 2
. As pH did not alter the formation of adduct in the presence of DNA, it is unlikely that pH would be a factor in adduct formation in vivo.
HOCl activated ABZ to a reactive intermediate that reacted with dGp to form dGp-ABZ. This was verified by ESI/MS/MS and 1H-NMR analyses. Aromatic amines are known to form reactive intermediates that reacted with dG to form C-8 adducts. Previous studies have demonstrated the formation of dGp-ABZ adduct and its presence in animals and humans exposed to benzidine (Kennelly et al., 1984; Lakshmi et al., 1995
; Martin et al., 1982
; Rothman et al., 1996
). This DNA adduct produces genotoxic lesions, causing mutations in various bacterial and mammalian test systems in vitro (Beland et al., 1983
; Heflich et al., 1986
; Melchior, Jr. et al., 1994
) and mutations in oncogenes of tumors induced in vivo by benzidine (Fox et al., 1990
). This suggests that dGp-ABZ could be involved in the initiation of benzidine-induced bladder cancer. A recent study has demonstrated dGp-ABZ formation following prostaglandin H synthase activation of ABZ (Lakshmi et al., 1998
). 32P-postlabeling in combination with HPLC confirmed that both HOCl and prostaglandin H synthase produce the same dGp-ABZ adduct. This is of interest because concentrations of DMPO that completely inhibit HOCl-mediated ABZ adduct formation are not effective in preventing prostaglandin H synthase activation (Zenser et al., 1999
). The latter involves a peroxygenation reaction, which was not observed with HOCl. Thus, although ABZ appears to be activated by two different mechanisms, the same adduct is formed. dGp-ABZ was quite stable at 70°C from pH 5.5 to 7.4, and only exhibited lability at extremely acidic or basic pHs. The stability of this adduct suggests that its recovery from biologic systems should be efficient.
The glycosidic linkage conformation of adducted DNA is an important factor in adduct persistence in vivo and may influence the biologic properties of the adduct. The two preferential conformations of the deoxynucleoside are termed anti and syn and are in rapid exchange. The relative proportion of these conformations depends upon substituents on either the sugar or the base. The chemical shift of the sugar 2' proton is a gauge of the preferred conformation of the glycosidic linkage because of the deshielding effect of the guanine N-3 atom in the syn conformation (Evans et al., 1980). The H-2' deoxyribose signals for dG-ABZ are found at 3.307 ppm; the shift for dG is at 2.456 ppm. This chemical shift is consistent with the preferred conformation of dG-ABZ being syn. Additional evidence that supports this postulated syn geometry comes from the ribose ring conformation, where marked downfield shifts of the OH-5' and OH-3' signals are observed. These results and conclusions are similar to that reported for N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (Turesky et al., 1992
). The relative conformations of 2'-deoxyguanosine 3'- and 5'-monophosphates may be affected by pH in a different manner and that may be, in part, responsible for the pH effect reported in Table 2
.
This study characterized the reaction of ABZ with HOCl to provide further insight into in vivo ABZ activation. HOCl can activate ABZ to form dGp-ABZ and may initiate adduct formation in peripheral white blood cells. Additional experiments are needed to determine whether inflammatory cells contribute to adduct formation by bladder epithelium. dGp-ABZ formation by the reaction of ABZ with HOCl provides an easy, convenient method for preparing this adduct standard.
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ACKNOWLEDGMENTS |
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NOTES |
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