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1.
Nutr Metab Cardiovasc Dis ; 29(1): 90-96, 2019 01.
Article in English | MEDLINE | ID: mdl-30522928

ABSTRACT

BACKGROUND AND AIM: Among elderly patients undergoing cardiac surgery, malnutrition is very common and related to muscle wasting known as sarcopenia. Cardiac surgery causes a further decline of nutritional status due to reduced dietary intake (DI); however, the impact of postoperative DI on functional recovery is unclear. METHODS AND RESULTS: We enrolled 250 consecutive patients undergoing cardiac surgery. Daily DI was measured between postoperative days 3 and 7. Patients were categorized as having sufficient or insufficient DI based on whether their DI met or was less than estimated total energy requirements. Functional capacity was measured using the 6-minute walking distance (6MWD) preoperatively and at discharge. Mean postoperative DI was 22.4 ± 3.0 kcal/kg/day, and postoperative DI was insufficient in 92 patients (36.8%). The prevalence of sarcopenia was not different by postoperative DI. Although there was no significant difference in preoperative 6MWD results (P = 0.65), the sufficient DI group had longer 6MWD at discharge than the insufficient DI group (P = 0.04). In multivariate regression analysis, preoperative poor nutritional status (ß = -0.29), duration of surgery (ß = -0.18), and postoperative DI (ß = 0.40) remained statistically significant predictors for improvement of 6MWD (P < 0.0001, adjusted R2 = 0.41). CONCLUSIONS: Postoperative DI was independently associated with functional recovery, but preoperative sarcopenia was not. Regardless of preoperative nutritional status or the presence of sarcopenia, aggressive nutritional intervention in the early stage after surgery helps support functional recovery.


Subject(s)
Cardiac Surgical Procedures/adverse effects , Eating , Energy Intake , Malnutrition/complications , Nutritional Status , Sarcopenia/complications , Aged , Aged, 80 and over , Exercise Tolerance , Female , Geriatric Assessment/methods , Humans , Male , Malnutrition/diagnosis , Malnutrition/physiopathology , Middle Aged , Nutrition Assessment , Recovery of Function , Risk Factors , Sarcopenia/diagnosis , Sarcopenia/physiopathology , Time Factors , Treatment Outcome , Walk Test
2.
Horm Metab Res ; 45(12): 856-61, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23979791

ABSTRACT

The aim of this study was to investigate the differences between rats and hamsters, Two of the most widely used experimental animals, with respect to the effects of microsomal membrane solubilization on the inhibition of liver 11ß-hydroxysteroid dehydrogenase (11ß-HSDI) enzyme by bile acids. Liver microsome fractions were prepared, and the 11ß-HSDI enzymatic activity was measured using cortisone as a substrate. The substrate and various concentrations of bile acids were added to the assay mixtures. After incubation, the products were extracted and analyzed using high-performance liquid chromatography. To investigate the effect of detergent on the inhibitory effects of bile acids, we conducted inhibition tests using Triton X-100-solubilized animal liver microsomes. When solubilized microsomes were used, all bile acids inhibited 11ß-HSDI from rats and hamsters to various degrees. 7α-Hydroxycholanoic acids (cholic acid and chenodeoxycholic acid) in particular had strong inhibitory activities. In hamsters, 7ß-hydroxycholanoic acid (ursodeoxycholic acid) was the strongest inhibitor among the bile acids tested, although its effect was not very strong. When nonsolubilized microsomes were used, deoxycholic acid did not inhibit but rather enhanced the enzymatic activity in both animals. Microsomal content of cholesterol and phospholipids are significantly different between rats and hamsters. Species differences in bile acid inhibition of nonsolubilized microsomes might be reflected not only by structural difference of bile acids, which affect membrane solubilization and enzyme activity directly, but also species difference in microsomal membrane lipid content.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Bile Acids and Salts/pharmacology , Cell Membrane/metabolism , Microsomes, Liver/enzymology , 11-beta-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Membrane/drug effects , Chenodeoxycholic Acid/pharmacology , Cricetinae , Male , Microsomes, Liver/drug effects , Rats , Rats, Wistar , Solubility , Species Specificity
3.
Phys Rev Lett ; 107(11): 113201, 2011 Sep 09.
Article in English | MEDLINE | ID: mdl-22026664

ABSTRACT

It was found that slow highly charged ions had a high ability to ionize F atoms on a F/Si(100)-2×1 surface and desorb F+ ions along the local bond direction. Actually, the F+ ion yields were proportional to the incident charge cubed, and the F+ ions were emitted along the Si-F bond directions showing a fourfold symmetry pattern. The trigger process of the F+ formation is discussed based on a charge transfer process of F 2p electrons by extending the classical over barrier model. Further, we found that the kinetic energy of highly charged ion induced F+ ions is lower than that of electron stimulated F+ ions caused by the removal of a F 2s electron.

4.
Phys Rev Lett ; 102(8): 085502, 2009 Feb 27.
Article in English | MEDLINE | ID: mdl-19257752

ABSTRACT

We present an experimental demonstration of an ingenious technique to control the alignment of the atomic internal state in the x-ray region using a periodic crystal field. The alignment directions of Ar16+ and Fe24+ ions were readily controlled by selecting the array of atomic planes using three-dimensional resonant coherent excitation, and were probed via the anisotropy of the deexcitation x-ray emission. We applied this method to a double resonance experiment, and succeeded in controlling the population of the specific magnetic substate in a Lambda-type three-level configuration.

5.
Phys Rev Lett ; 101(11): 113201, 2008 Sep 12.
Article in English | MEDLINE | ID: mdl-18851279

ABSTRACT

We report the Autler-Townes doublet demonstrating a novel type of coherent interaction of atoms not with photons but with a periodic crystal field when the atom is in flight through a crystal at high velocity. It was observed by the nonoptical X-VUV (vacuum-ultraviolet) double resonance of three-dimensional resonant coherent excitation with good coherence. The states strongly coupled in the VUV region were probed by the excitation in the x-ray region. The characteristic spectra are well interpreted by an analogy of the dressed atom concept often adopted for the atom-photon interaction.

6.
Phys Rev Lett ; 100(20): 203402, 2008 May 23.
Article in English | MEDLINE | ID: mdl-18518532

ABSTRACT

We report here the radial compression of a large number of antiprotons ( approximately 5 x 10(5)) in a strong magnetic field under ultrahigh vacuum conditions by applying a rotating electric field. Compression without any resonant structures was demonstrated for a range of frequencies from the sideband frequency of 200 kHz to more than 1000 kHz. The radial compression achieved is a key technique for synthesizing and manipulating antihydrogen atoms and antiprotonic atoms.

7.
Phys Rev Lett ; 97(14): 145502, 2006 Oct 06.
Article in English | MEDLINE | ID: mdl-17155267

ABSTRACT

We have measured deexcitation x rays emitted from the resonant coherently excited 2(1)P(1) state of heliumlike Fe24+ ions of 423 MeV/amu, planar channeling through a Si crystal. Large anisotropy in the angular distribution of deexcitation x-ray emission is observed: the x-ray emission in the direction parallel to the channeling plane is favored by a factor of 2 compared to the perpendicular direction. This anisotropy originates from the direction of the periodic crystal field, which populates specific m states in resonant coherent excitation and aligns the excited states.

8.
Phys Rev Lett ; 97(13): 135503, 2006 Sep 29.
Article in English | MEDLINE | ID: mdl-17026044

ABSTRACT

We have observed resonant coherent excitation (RCE) of H-like Ar(17+) ions traveling through a 1 microm-thick Si crystal at an energy of 391 MeV/u in the nonchanneling condition. A three-dimensional periodic array of atomic planes induces RCE of the nonchanneling ions. The high energy heavy ions together with the thin crystal allow us to observe this new RCE through the measurements of the charge-state distribution of the emerging ions. The observed resonances are much narrower than those of planar-channeling ions due to the absence of the large Stark shift caused by the planar potential.

9.
Phys Rev Lett ; 95(25): 253003, 2005 Dec 16.
Article in English | MEDLINE | ID: mdl-16384456

ABSTRACT

We demonstrate that transitions between Zeeman-split sublevels of Rb atoms are resonantly induced by the motion of the atoms (velocity: approximately 100 m/s) in a periodic magnetostatic field (period: 1 mm) when the Zeeman splitting corresponds to the frequency of the magnetic field experienced by the moving atoms. A circularly polarized laser beam polarizes Rb atoms with a velocity selected using the Doppler effect and detects their magnetic resonance in a thin cell, to which the periodic field is applied with the arrays of parallel current-carrying wires.

10.
Phys Rev Lett ; 94(2): 023401, 2005 Jan 21.
Article in English | MEDLINE | ID: mdl-15698175

ABSTRACT

We have used a radio frequency quadrupole decelerator to decelerate antiprotons emerging from the CERN Antiproton Decelerator from MeV- to keV-scale energy, and collected five decelerated pulses in a multiring trap. Some 5 x 10(6) antiprotons were stacked in this way. Cooling of the trapped antiprotons by a simultaneously trapped electron plasma was studied nondestructively via shifts in plasma mode frequencies. We have also demonstrated the first step in extracting a 10-500 eV antiproton beam from the trap.

11.
Phys Rev Lett ; 93(19): 195001, 2004 Nov 05.
Article in English | MEDLINE | ID: mdl-15600840

ABSTRACT

A new positron accumulation scheme compatible with ultrahigh vacuum conditions has been developed, which is realized by preparing a high density electron plasma as high as approximately 10(11) cm(-3) and an ion cloud as energy absorbers. The present accumulation rate normalized by the intensity of 22Na positron source is (3.6+/-0.3)x10(2)e(+)/s/mCi, which is more than one and a half orders of magnitude higher than other ultrahigh vacuum compatible schemes so far reported.

12.
Breast Cancer Res Treat ; 88(1): 1-8, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15538040

ABSTRACT

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher (p < 0.01) and TG was significantly lower (p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Lipids/blood , Tamoxifen/pharmacology , Toremifene/pharmacology , Adult , Aged , Aged, 80 and over , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Chemotherapy, Adjuvant , Female , Humans , Lipid Metabolism , Middle Aged , Postmenopause
13.
Phys Rev E Stat Nonlin Soft Matter Phys ; 70(2 Pt 2): 026501, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15447603

ABSTRACT

Radial compression of a proton cloud was performed in a multiring trap which was designed to trap and cool a large number of antiprotons for the production of low-energy ( 10-1000 eV ) antiproton beams. The resonance frequency for the radial compression was almost constant from 3 x 10(5) to 3 x 10(6) protons. The collision process of the trapped protons was also investigated to estimate the energy of the protons inside the trap. This technique will be applied to the ASACUSA experiment at the antiproton decelerator, CERN, to extract ultraslow antiprotons with good emittance.

14.
Phys Rev E Stat Nonlin Soft Matter Phys ; 65(4 Pt 2B): 046410, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12006026

ABSTRACT

Electron cooling of energetic protons in a multiring trap was investigated experimentally with a tank circuit monitoring electron-plasma oscillations in the trap. The energy of protons was determined by time-of-flight measurements. It is found that a simple model can explain the qualitative behavior of both electron and proton energy when the initial energy of protons is less than 2 keV. Monitoring the electron-plasma temperature with a tank circuit can be an effective tool when energetic particles are electron cooled in a multiring trap.

15.
Chem Res Toxicol ; 14(8): 1006-13, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11511174

ABSTRACT

A new HPLC gradient system was developed for (32)P-postlabeling analysis to identify and quantify hepatic tamoxifen-DNA adducts of rats and mice treated with tamoxifen. Four stereoisomers of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG(3')(P)-N(2)-TAM), alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen (dG(3')(P)-N(2)-N-desmethyl-TAM), and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide (dG(3')(P)-N(2)-TAM N-oxide) were prepared by reacting either alpha-acetoxytamoxifen, alpha-acetoxy-N-desmethyltamoxifen or alpha-acetoxytamoxifen N-oxide with 2'-deoxyguanosine 3'-monophosphate, and used as standard markers for (32)P-postlabeling/HPLC analysis. Our HPLC gradient system can separate the above 12 nucleotide isomers as nine peaks; six peaks representing two each trans epimers (fr-1 and fr-2) of dG(3')(P)-N(2)-TAM, dG(3')(P)-N(2)-N-desmethyl-TAM and dG(3')(P)-N(2)-TAM N-oxide, and three peaks representing a mixture of two cis epimers (fr-3 and fr-4) of nucleotides. Tamoxifen was given to female F344 rats and DBA/2 mice by gavage at doses of 45 mg/kg/day and 120 mg/kg/day, respectively, for 7 days. Totally 15 and 17 tamoxifen-DNA adducts were detected in rats and mice, respectively; among them 13 adducts were observed in both rats and mice. trans-dG-N(2)-TAM (fr-2) and trans-dG(3')(P)-N(2)-N-desmethyl-TAM (fr-2) were two major adducts in both animals. Except for these two adducts, trans-dG-N(2)-TAM N-oxide (fr-2) was the third abundant adduct that accounted for 6.4% of the total adducts in mice, while this accounted for only 0.3% in rats. A trans-isomer (fr-1) and cis-isomers (fr-3 and -4) of dG(3')(P)-N(2)-TAM, dG(3')(P)-N(2)-N-desmethyl-TAM and dG(3')(P)-N(2)-TAM N-oxide were also detected as minor adducts in both animals except for cis-form of dG-N(2)-TAM N-oxide in rats. Although the administered dose for rats was 2.7-fold less than that for mice, the total adduct level of rats (216 adducts/10(8) nucleotides) were 3.8-fold higher than mice (56.2 adducts/10(8) nucleotides). Thus, these three types of tamoxifen adducts accounted for 95.0 and 92.5% of the total DNA adducts of the rats and mice, respectively. The formation of tamoxifen adducts primarily resulted from alpha-hydroxylation of tamoxifen.


Subject(s)
Carcinogens/chemistry , DNA Adducts/analysis , Tamoxifen/chemistry , Animals , Carcinogens/analysis , Chromatography, High Pressure Liquid/methods , Hydroxylation , Liver/pathology , Mice , Phosphorus Radioisotopes , Rats , Rats, Inbred F344 , Sensitivity and Specificity , Tamoxifen/analysis
16.
Mol Biochem Parasitol ; 116(1): 73-9, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11463468

ABSTRACT

We have identified the 2-Cys peroxiredoxin (PfPrx-1) from the human malaria parasite Plasmodium falciparum. The PfPrx-1 showed the highest identity at amino acid level to the type II Prx among the currently known six subfamilies of mammalian Prx. The sequence identity between the PfPrx-1 and the previously reported 1-Cys Prx of P. falciparum (PfPrx-2), which corresponded to mammalian type VI Prx, was 25%. This suggests that the parasite possesses two Prx subfamilies. The PfPrx-1 showed significant sequence similarities with those of 2-Cys peroxiredoxins of plants in the BLASTX search. This may reflect the consequences of a genetic transfer from an algal endosymbiont to the parasite nucleus during evolution. The recombinant PfPrx-1 protein (rPfPrx-1) was expressed as a histidine fusion protein in Escherichia coli and purified with Ni chromatography. The rPfPrx-1 existed as dimers under non-reducing conditions and dissociated into monomers in the presence of dithiothreitol. The PfPrx-1 protein also exists as a dimer in the parasites themselves. The reduction of the oxidized enzyme by the donation of electrons from E. coli thioredoxin (Trx)/Trx reductase system was demonstrated in its reaction with H(2)O(2), using the rPfPrx-1 protein. These results suggested that the PfPrx-1 can act as a terminal peroxidase of the parasite Trx system. An elevated expression of the PfPrx-1 protein seen in the trophozoite, the stage with active metabolism, suggests an association of the parasite Trx system with its intracellular redox control.


Subject(s)
Peroxidases/genetics , Plasmodium falciparum/genetics , Amino Acid Sequence , Animals , Antioxidants , Cloning, Molecular , Molecular Sequence Data , Peroxiredoxin VI , Peroxiredoxins , Plasmodium falciparum/enzymology , Plasmodium falciparum/pathogenicity , Protozoan Proteins/genetics , Sequence Analysis, DNA , Sequence Homology, Amino Acid
17.
J Electrocardiol ; 33(3): 225-31, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10954375

ABSTRACT

High-resolution signal-averaged electrocardiography (Hi-Res ECG) has been found useful in measuring ventricular late potentials for identifying patients prone to life-threatening ventricular arrhythmias. Several studies have reported cut-off values (normal limits) of Hi-Res ECG parameters, including sex-specific limits, for adult population. However, there are no such studies reporting such limits in the Japanese population. Hi-Res ECGs were recorded from 482 normal healthy patients (204 men; 278 women) with no cardiac disease and normal electrocardiogram. Three Hi-Res ECG parameters filtered QRS duration (FQRSD), low amplitude signal duration under 40 microV of terminal QRS (LASD), and root mean square voltage in the terminal 40 milliseconds (RMSV) were analyzed. FQRSD was longer in men than in women (P < .0001). RMSV was larger in men than in women (P < .0001). There was no significant difference in LASD between men and women. The upper limit (90th percentile) of FQRSD was 116 milliseconds for women. The upper limit of LASD was 42 milliseconds for both men and women. The lower limit (10th percentile) of the RMSV was 14 microV for both men and women. There was no significant difference in the distributions of the Hi-Res ECG parameters between our study and an earlier study on mostly whites from the United States and Europe. The upper limits (90th percentile) of FQRSD and LASD in the Japanese normal patients were nearly the same as for whites. But, the lower limit (10th percentile) of RMSV in our Japanese normals was significantly smaller than that for whites. Therefore, it may be necessary to use race-specific normal limits for late potential analysis. Criteria for abnormal late potentials (defined as abnormal values in at least 2 of the 3 Hi-Res ECG parameters) were met in 18 of 482 (3.7%) normal healthy patients. Further studies are needed to evaluate the role of these criteria in identifying cardiac patients with life-threatening arrhythmias in the Japanese population.


Subject(s)
Electrocardiography/methods , Adolescent , Adult , Aged , Anthropometry , Female , Humans , Japan , Male , Middle Aged , Reference Values , Sex Characteristics
18.
Carcinogenesis ; 21(9): 1737-44, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10964106

ABSTRACT

Tamoxifen-DNA adducts detected in the liver of mice treated with tamoxifen have not yet been identified. In the present study a new type of tamoxifen-DNA adduct, four stereoisomers of alpha-(N:(2)-deoxyguanosinyl)tamoxifen N:-oxide 3'-monophosphate (dG(3'P)-N:(2)-TAM N:-oxide) were prepared as standard DNA adducts by reacting 2'-deoxyguanosine 3'-monophosphate with trans-alpha-acetoxytamoxifen N:-oxide in addition to four stereoisomers of alpha-(N:(2)-deoxyguano- sinyl)tamoxifen 3'-monophosphate (dG(3'P)-N:(2)-TAM) that was reported previously. Liquid chromatography-electrospray ionization-mass spectrometry of the reaction products gave the most abundant ion at m/z 731 ([M - H](-)), which corresponded to dG(3'P)-N:(2)-TAM N:-oxide. The modified products digested by alkaline phosphatase corresponded to the isomers of dG-N:(2)-TAM N:-oxide whose structures were identified previously by mass spectrometry and nuclear magnetic resonance. Using these standard markers, we analyzed the hepatic DNA adducts of female DBA/2 mice treated with tamoxifen at a dosage of 120 mg/kg/day for 7 days by (32)P-post-labeling coupled with an HPLC/radioactive detector. Mixtures of eight isomers of dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N-oxide were separated into six peaks, since each of the cis epimers were not separated under the present HPLC conditions. Nine adducts were detected in all liver samples of mice. An epimer of trans-dG(3'P)-N:(2)-TAM was detected as the principal DNA adduct at a level of 29.0 adducts/10(8) nucleotides, which accounted for 53.3% of the total tamoxifen-DNA adducts. Lesser amounts of cis-dG(3'P)-N:(2)-TAM (2.8%) were also observed. An epimer of the trans-dG(3'P)-N:(2)-TAM N:-oxide (3.9 adducts/10(8) nucleotides) was detected as the third biggest adduct (7.2% of the total). The cis-dG(3'P)-N:(2)-TAM N:-oxide (0.4 adducts/10(8) nucleotides) accounted for 0.7% of the total. Thus, dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N:-oxide were identified in tamoxifen-treated mouse liver.


Subject(s)
DNA Adducts/analysis , DNA/metabolism , Liver/metabolism , Tamoxifen/analogs & derivatives , Tamoxifen/analysis , Tamoxifen/metabolism , Animals , Chromatography, High Pressure Liquid , DNA/drug effects , Deoxyguanine Nucleotides/chemistry , Female , Isomerism , Liver/chemistry , Mass Spectrometry , Mice , Mice, Inbred DBA , Tamoxifen/chemistry
19.
Insect Biochem Mol Biol ; 30(3): 253-8, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10732993

ABSTRACT

Buchnera, endosymbiotic bacteria of aphids possess many genomic copies per cell. In this study, we estimated genomic copy number per Buchnera cell from host insects at various developmental stages and of two different morphs, apterae and alatae, by fluorimetry and real-time quantitative PCR. The results indicated that the genomic copy number of Buchnera increased during postembryonic development of insects to adulthood, and that it decreased during the host's ageing. In Buchnera from alatae, the genomic copy number per cell was about twice as many as in those from apterae. DAPI-staining showed that the distribution of the genomic DNA in the Buchnera cells from old insects tended to aggregate, suggesting that intracellular structure of the genomic DNA of Buchnera varies in response to the physiological conditions of their host.


Subject(s)
Aphids/microbiology , Buchnera/genetics , Genome, Bacterial , Animals , Aphids/growth & development , DNA, Ribosomal , Gene Dosage , Intracellular Fluid , Polymerase Chain Reaction/methods , RNA, Ribosomal, 16S , Symbiosis
20.
Chem Res Toxicol ; 12(11): 1083-9, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10563834

ABSTRACT

DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endometrial cancer in breast cancer patients taking tamoxifen and healthy women enrolled in a tamoxifen chemopreventive trial. To determine whether DNA adducts were formed by tamoxifen, trans- and cis-alpha-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and alpha-hydroxytamoxifen N-oxide. When alpha-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by (32)P-postlabeling coupled with HPLC. The total amount of DNA adducts formed by trans-alpha-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-alpha-acetoxytamoxifen N-oxide reacted with 2'-deoxyguanosine, resulting in the formation of three adducts (fr-1, fr-2-1, and fr-2-2). These products were studied using mass spectroscopy and proton magnetic resonance spectroscopy. fr-1 was identified as a mixture of the epimers of trans-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.


Subject(s)
Antineoplastic Agents, Hormonal/chemistry , DNA Adducts/chemistry , Tamoxifen/analogs & derivatives , Tamoxifen/chemistry , Acetylation , Chromatography, High Pressure Liquid , Spectrometry, Mass, Fast Atom Bombardment , Sulfates/chemistry
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