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| 1.
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Hayakawa, Kazuichi ; Miyoshi, Yasuko ; Kurimoto, Hiroaki ; Matzushima, Yuko ; Takayama, Nariaki ; Tanaka, Seishi ; Miyazaki, Motoichi ; 早川, 和一 ; 三好, 裕子 ; 栗本, 博昭 ; 松島, 優子 ; 高山, 成明 ; 田中, 星司 ; 宮崎, 元一
概要:
金沢大学理工研究域自然システム学系<br />A HPLC determination method for methamphetamine (MA) and its metabolites in the urine samples of
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abusers has been developed. MA, amphetamine (AP), norephedrine (NE), p-hydroxymethamphetamine (pOHMA), p-hydoroxyamphetamine (pOHAP) and an internal standard, namely β-phenylethylamine (PEA) were derivatized with dansyl chloride. They were separated on a reversed phase column with gradient elution using an acetonitrile/tetrahydrofuran/imidazole buffer mobile phase and chemilumigenically determined using bis(2, 4, 6-trichlorophenyl)-oxalate/hydrogen peroxide as post column reagents. The lower determination limits were as low as 1×10-14-3×10-14mol. AP, NE, pOHAP and PEA were derivatized with naphthalene-2, 3-dicarboxaldehyde, and were separated on a reversed phase column using an acetonitrile/imidazole buffer mobile phase and chemilumigenically determined. The lower determination limits were 3×10-16-1.5×10-15mol. Enzymatic hydrolysis of glucuronides of pOHMA (pOHMAG) and pOHAP (pOHAPG) allowed them to be determined as pOHMA and pOHAP, respectively. After adjusting the pH of the urine samples to 10.5 and adding PEA, all metabolites except glucuronides were extracted quantitatively into chloroform-isopropanol (3 : 1). Utilizing the two methods, MA and all metabolites were determined in urine samples of MA abusers. The tendency, in order of decreasing concentration was : [MA]>[A]>[pOHMAG]>[pOHMA]>[NE]>[pOHAPG]>[pOHAP]. Although ephedrine (EP) was detected in several samples, it was not considered to be a metabolite of MA but rather a component derived from cough medicine.
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| 2.
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大辻, 雅彦
概要:
金沢大学 医 法医<br />1)わが国で使用頻度が高い向精神薬,催眠・鎮静薬,抗ヒスタミン薬及び局所麻酔薬等から42種の薬物・代謝物を選び,それらを蒸留水或いは血清や尿に実験的に添加し,REMEDi-HSで分析したところ,4種の酸性薬物を
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除く38種の薬物や代謝物の分析が可能であり,一部新規に薬物同定ライブラリーに登録することで,38種の薬物全てが定性的に同定可能となった.又,リドカイン,プリロカイン,メピバカインなど10種の局所麻酔薬及びその代謝物,更に覚醒剤メタンフェタミンやその代謝物及び関連化合物であるアンフェタミン,メチルエフェドリン,エフェドリンは,同一検体での同時スクリーニングが可能であった. 2)REMEDi-HSを用い53例の救急患者及び79例の剖検例の試料からの薬毒物分析を施行したところ,各々46例,61例で何らかの薬物が検出され,その分析結果は死因決定や確認,或いは薬物中毒の診断や治療方針の決定に重要な役割を果たした
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| 3.
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本間, 啓子 ; 菅原, 清 ; 加藤, 聖 ; 馬渡, 一浩
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金沢大学 医 検査技術<br />原著論文
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| 4.
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本間, 啓子 ; 馬渡, 一浩
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金沢大学 検査技術<br />原著論文
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| 5.
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Hitomi, Yoshiaki ; Okuda, Junna ; Nishino, Hirohito ; Kambayashi, Yasuhiro ; Hibino, Yuri ; Takemoto, Kei ; Takigawa, Tomoko ; Ohno, Hideki ; Taniguchi, Naoyuki ; Ogino, Keiki
概要:
金沢大学医薬保健研究域医学系<br />3-Nitrotyrosine (NTyr) is considered as a biomarker of the generation of reactive nitrogen species (
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RNS). However, it is still difficult to determine its concentration in biological samples. To develop a reliable and high-throughput method, we optimized the conditions for high performance liquid chromatography and electrochemical detection (HPLC-ECD). The best separation of NTyr was achieved using a highly acidic mobile phase (pH 2.5). The concentration of protein-bound NTyr in plasma protein was 593.6 ± 53.8 fmol/mg in rats treated with lipopolysaccharide (LPS) and 114.4 ± 27.6 fmol/mg in control. After intravenous administration of in vitro-nitrated plasma protein, NTyr concentration decreased; the half-life was 63.4 ± 16.8 h. Consistently, protein-bound NTyr concentration in plasma after LPS treatment declined gradually, but was detectable for 1 week. Our protocol is reproducible and suitable for analysing multiple clinical samples to study RNS production in vivo. © 2007 The Japanese Biochemical Society.
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| 6.
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Shimada, Kazutake ; Ohishi, Kazuo ; Nambara, Toshio
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金沢大学大学院自然科学研究科分子作用学<br />金沢大学薬学部
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| 7.
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Mizuguchi, Tatsuhito ; Shibayama, Yujin ; Mitamura, Kuniko ; Shimada, Kazutake
概要:
金沢大学大学院自然科学研究科分子作用学<br />金沢大学薬学部<br />Contribution of glucuronic acid and sulfonic acid moieties during the photocatalyt
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ic degradation of estrogen conjugates, one of the endocrine disrupting chemicals, has been investigated. Estrogens were subjected to photocatalytic degradation using titanium dioxide immobilized on glass beads as a catalyst, whose time courses were measured by HPLC or liquid chromatography (LC)/MS/(MS). Estradiol and estrone, which have an unconjugated phenolic hydroxy group at the C-3 position, were gradually degraded by UV irradiation and nearly disappeared within 6 hr. 3-Desoxyestradiol, which does not have a phenolic hydroxy group at C-3 position, was also degraded like estradiol. The corresponding 17- or 3-glucuronide was degraded faster than the respective genin, estradiol or estrone. The double conjugate, estriol 3-sulfate 16-glucuronide, was also easily degraded within 3 hr. On the other hand, the degradation of estrogen 3-sulfate did not start within 2.5 hr but the reaction was completed within 6 hr. These data showed that the glucuronic acid moiety on the estrogen skeleton and sulfonic acid moiety at phenolic hydroxy group play an important role for this degradation reaction.
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| 8.
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Yvonne, Chondo ; Ying, Li ; Fumiya, Makino ; Ning, Tang ; Akira, Toriba ; Takayuki, Kameda ; Kazuichi, Hayakawa
概要:
A new method for the analysis of selected nitropolycyclic aromatic hydrocarbons (NPAHs) at ultra-trace levels in water s
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amples is proposed. Particulate NPAHs were collected on a GC glass fiber filter. Soluble NPAHs were collected on a C18 Empore disk. After simple clean-up and concentration of NPAHs in both phases, the NPAHs were analyzed using HPLC equipped with clean-up, reducer, concentration and chemiluminescence detection units. The proposed method showed good linear calibration curves with correlation coefficients (r2) ranging from 0.9954 to 0.9998. The limits of detection ranged from 0.013 to 0.15 nmol/L (soluble NPAHs) and from 0.01 to 0.13 nmol/L (particulate NPAHs) for 5 NPAHs [(9-nitroanthracene, 1-nitropyrene, 6-nitrochrysene (6-NC), 7-nitrobenz[a]anthracene and 6-nitrobenzo[a]pyrene] having 3 to 5 rings analyzed, when 1.5 L of water sample was used. The repeatability for soluble NPAHs ranged between 4.2 and 6.8% (n=5), while for particulate NPAHs, it varied between 2.2 and 2.8% (n=5). The proposed method successfully determined the above NPAHs expect 6-NC in river water samples, suggesting that this method is suitable for the ultra-trace analysis of NPAHs in water samples.
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| 9.
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Li, Ying ; Yoshida, Shota ; Chondo, Yvonne ; Nassar, Hossam ; Tang, Ning ; Araki, Yuki ; Toriba, Akira ; Kameda, Takayuki ; Hayakawa, Kazuichi
概要:
An on‑line concentration and fluorescence determination HPLC for polycyclic aromatic hydrocarbons (PAHs) in seawater was
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proposed. An online concentration column packed with octadecyl polyvinyl alcohol polymer, a pump and a column switching valve were introduced in the conventional HPLC with a fluorescence detector. Only 1.0–100 mL seawater sample was introduced into the concentration column at 1.0 mL min−1 without any other pretreatment except filtration. Then the trapped PAHs totally flew into the separation column and eluted separately to be detected fluorogenically. The proposed method had good linearity with correlation coefficients (r) ranged from 0.951 to 0.998, and limits of detection ranged from 0.002 to 0.50 ng L−1 for 15 PAHs as 100 mL seawater was loaded. The sensitivity of the method was 10 to 100 times higher than those reported by other works. The proposed method was applied to the determination of PAHs in the seawater samples collected in the Japan Sea with satisfactory results and to check the present benzo[a]pyrene concentration at the beaches in Noto peninsula, Japan polluted with C-heavy oil spilled from the tanker in 1997.
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| 10.
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鳥羽, 陽 ; 本間, 千春 ; 宇於崎, 和香 ; Chuesaard, Thanyarat ; 唐, 寧 ; 早川, 和一
概要:
A high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the quantification
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of polycyclic aromatic hydrocarbons (PAHs) in cigarette mainstream and sidestream smoke particulates. Fifteen kinds of PAHs classified as priority pollutants by the US EPA were quantified with six perdeuterated PAHs as internal standards. The smoke filter samples obtained from 3 brands of cigarettes using standardized smoking conditions were extracted with dichloromethane, and then treated with tandem solid phase extraction cartridges (Silica and Neutral Alumina). The limits of detection ranged from 0.24 to 2.2 pg, and were more sensitive than those by GC-MS. The analytes were quantified by using the internal standards, and the developed method achieved sufficient reproducibility and accuracy. The PAH levels in mainstream and sidestream smoke from 3 cigarette brands were in the range of 0.2 – 305 ng cigarette−1 and 26.4 – 6160 ng cigarette−1, respectively. The total PAH content in sidestream smoke was more than 10 times higher compared with that of mainstream smoke. This method should be useful as an optional analytical method to quantify PAHs in cigarette smoke particulates.
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| 11.
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Morisaki, Hiroshi ; Nakamura, Shiho ; Tang, Ning ; Toriba, Akira ; Hayakawa, Kazuichi
概要:
Benzo[c]fluorene (BcFE) concentrations in benzene/ethanol extracts of airborne particulates were determined by high-perf
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ormance liquid chromatography (HPLC) with fluorescence detection. HPLC conditions were as follows: columns, two ZORBAX Eclipse PAH (4.6 i.d. × 250 mm, 3.5 μm) and one Inertsil ODS-P (4.6 i.d. × 250 mm, 5 μm) in series; mobile phase, acetonitrile–water (98:2, v/v), 0.3 mL/min; detection wavelengths, excitation 309 nm, emission 354 nm. Particulate-phase BcFE concentrations in the atmosphere varied seasonally (winter > summer). The concentrations were 11000 ± 6100 pg m−3 (winter) and 40 ± 12 pg m−3 (summer) in Beijing, China, and 13 ± 5.0 pg m−3 (winter) and 2.7 ± 0.52 pg m−3 (summer), in Kanazawa, Japan. In both cities, the particulate-phase BcFE concentration in the atmosphere was lower than that of benzo[a]pyrene (BaP) by a factor of 0.03 – 0.43. However, the mutagenic contribution of particulate-phase BcFE in the atmosphere in winter calculated from the mutagenicity relative potency factor was greater than that of BaP.
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| 12.
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Hayakawa, Kazuichi ; Butoh, Mizuka ; Hirabayashi, Yukiko ; Miyazaki, Motoichi
概要:
1, 3-, 1, 6-, 1, 8-Dinitropyrenes (DNPs) and 1-nitropyrene (1-NP) in exhaust particulates from idling gasoline and diesel engines were determined using off-line sodium hydrosulfide reduction followed by HPLC with chemiluminescence
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detection. The mean concentrations of 1, 3-, 1, 6-, 1, 8-DNPs and 1-NP were 0.22, 0.44, 0.35 and 1.8 pmol/mg, respectively, in gasoline particulates (n=8) and 0.23, 0.23, 0.21 and 51 pmol/mg, respectively, in diesel particulates (n=7). Although the concentrations of DNPs were lower than that of 1-NP in both gasoline and diesel particulates, they cannot be dismissed as negligible because of their extremely high mutagenicity. There was a tendency toward higher DNPs and 1-NP concentrations in particulates, with the lowering of particulate concentration in exhaust gas. The total amount of DNPs and 1-NP emitted from diesel engine vehicles was considered to be remarkably higher than that of gasoline engine vehicles.
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| 13.
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松永, 明信 ; 山本, 敦 ; 水上, 英一 ; 早川, 和一 ; 宮崎, 元一
概要:
A high-performance liquid chromatographic method using post column reaction system was established for the determination
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of polyphosphates (PP). Linear polyphosphates with the range of polymerization from 2 to 9 (P2-P9) could be separated on an anion exchange column, TSK GEL DEAE-5PW (Toyo Soda), with 0.01 M HNO3 containing NaNO3 as a mobile phase at flow rate of 1.0 ml/min, with a linear gradient in NaNO3 concentration at one hour intervals. PP were detected as the decrease of absorbance at 500 nm of ferric-sulfosalicylate complex by means of an on-line post column reaction at room temperature, with 0.5 mM FeCl3 containing 2.5 mM sulfosalicylic acid as reaction reagent at flow rate of 0.5 ml/min. The proposed method was applied to the analysis of 30 different commercial products of soft drinks. The pretreatment only necessary after mixing the sample with an equal volume of 0.01 M HNO3 was filtration through 0.45 μm pore size filter. P2-P6 (total 0.231 g/kg) and P2-P4 (0.070 g/kg) were found from 2 kinds of the samples, respectively. The determination limit was 0.02 m mol/kg for all of the PP.
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| 14.
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早川, 和一
概要:
Recent studies on the three new photometric detection in the liquid chromatographic methods have been reviewed. The detector and systems based on these detection theories and their applications to several fields have been also
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described. Differential photometric detection using UV-visible absorbing eluents enabled us to examine the retention and detection mechanism of sample and eluent ions in ion exchange chromatography. Photometric detection in ion chromatography determined transparent ionic compounds using indirect photometric detection mode of this theory. This method was useful for many samples such as environmental water and foods. Polarized photometric detection method has been developed by introducing two polarizers on either side of the UV-visible absorbance detector flow cell. The monitor determined optically active compounds as the change in absorbance. This method was applied for determining food additives such as sugars and organic compounds. A HPLC system with a chemiluminescence detector has been developed for the determination of trace levels of mutagenic nitroarenes such as 1, 3-, 1, 6-, 1, 8-dinitropyrenes and 1-nitropyrene. Utilizing this system, their exhaust from vehicles and behavior in air were examined in detail. This system was also used for determining methamphetamines in abuser urine and hair.
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| 15.
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Toriba, Akira ; Hayakawa, Kazuichi
概要:
Polycyclic aromatic hydrocarbons (PAHs) and itropolycyclic aromatic hydrocarbons (NPAHs) are widespread carcinogenic compounds that arise from occupational, environmental and dietary sources. The metabolites of PAHs and NPAHs in
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biological fluids have been investigated as potential biomarkers for assessing human exposure to them, and, particularly, urinary metabolites are the excellent candidates due to the non-invasiveness and convenience of collecting the sample. Here we describe HPLC methods for accurately determining one type of these metabolites, monohydroxy PAHs (OHPAHs). The developed method was applied to the urine samples of non-smoker taxi drivers, traffic police officers and rural villagers of Chiang Mai, Thailand. The results showed higher urinary concentrations of OHPAHs in rural villagers, suggesting the higher respiratory exposure to PAHs contained in smoke from biomass burning. On the other hand, 1-nitropyrene (1-NP) is one of the most abundant NPAHs in diesel exhaust particulate matter (DEP). We also developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining urinary 1-NP metabolites. 1-NP metabolites were quantified in urine from healthy subjects. 6- and 8-Hydroxy-N-acetyl-1-aminopyrenes (OHNAAPs) and 6- and 8-hydroxy-1-nitropyrenes (OHNPs) were the most abundant 1-NP metabolites in human urine. The presence of OHNAAPs and OHNPs in human urine was demonstrated for the first time.
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| 16.
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Ohno, Takanori ; Toriba, Akira ; Kameda, Takayuki ; Tang, Ning ; Hayakawa, Kazuichi
概要:
金沢大学医薬保健研究域薬学系<br />To measure the actual exposure of a person to 1-nitropyrene (1-NP) in airborne particulate matter, i
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t is considered more accurate to collect air samples with a portable air sampler than to sample at a fixed location. However, because the portable samplers can sample only small volumes, a sensitive method is needed to analyze the compounds that are collected on a filter. Here we describe a high-performance liquid chromatographic (HPLC) method with fluorescence detection that is sensitive and precise enough for use with portable air samplers. The developed column-switching system successfully removed the interfering substances in the samples with only a simple pretreatment. To improve the precision of the measurement, deuterated 1-NP was used as an internal standard, and it eluted immediately prior to 1-NP with sufficient resolution (Rs, 1.50). The detection limit was 0.32 fmol/injection, and the calibration range was from 2 to 100 fmol. The proposed method was applied to determining 1-NP in fine airborne particulate matter (PM2.5) at two sites with low pollution levels. 1-NP was detected in all samples at concentrations in the low fmol/m3 range. The proposed method has enough sensitivity and precision to determine 1-NP in the limited air volume of the portable sampler. © 2009 Elsevier B.V. All rights reserved.
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| 17.
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村橋, 毅 ; 早川, 和一 ; 岩本, 侑子 ; 宮崎, 元一
概要:
金沢大学医薬保健研究域薬学系<br />A simultaneous determination method for polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs (NPAH
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s) in airborne particulates was developed. Airborne particulates were extracted with benzene/ethanol, cleaned up by liquid-liquid partition, refluxed in the presence of NaSH and then the resultant solution was injected into an HPLC system. The system was hybridized into two systems with different optimum conditions for PAHs and NPAHs by introducing a switching valve and a mini separation column. Mobile phases were acetonitrile/water (75 : 25) for PAHs, and acetonitrile/imidazole HClO_4 buffer (1 : 1) for NPAHs and the postcolumn reagent solution for NPAHs was an acetonitrile solution containing bis(2,4,6-trichlorophenyl)oxalate and H_2O_2. By this method, four NPAHs (1,3-, 1,6-, 1,8-dinitropyrenes and 1-nitropyrene) and eight PAHs (fluoranthene, pyrene, benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene and coronene) in sub-milligram quantities of airborne particulates were determined chemilumigenically and fluorogenically, respectively using 2-fluoro-7-nitrofluorene as an internal standard within sixty minutes.
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| 18.
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金, 明姫 ; 西尾, 忠 ; 嶋田, 努 ; 竹田, 和喜 ; 横川, 弘一 ; 宮本, 謙一
概要:
A fully automated high-performance liquid chromatography system with column-switching was evaluated to determine the con
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centration of zonisamide (ZNS) in human plasma. After the plasma sample was diluted to 10-times with the mobile phase, the sample (101μL) was injected into the column-switching system without pretreatment. ZNS was detected by ultraviolet absorption at 246 nm. The calibration curve of ZNS was linear and ranged from 1.57 to 50μg/mL of plasma. The coefficients of variation in the within-run (n=5) and the between-run (5 days) precisions of ZNS were below 5 %. The limit of quantification was 0.5pg/mL in 1 μL of human plasma. A good correlation was found between the data obtained by this system and the ELISA system using Markit-M Excegran (r=0.956) or the solid-phase-extraction HPLC method (r=0.985). This system for ZNS is thus considered to be a very useful measurement for therapeutic drug monitoring because of its high sensitivity, rapidity and low cost compared with other measurement systems.
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| 19.
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金, 明姫 ; 西尾, 忠 ; 嶋田, 努 ; 竹田, 和喜 ; 横川, 弘一 ; 宮本, 謙一
概要:
A fully automated high-performance liquid chromatography system with column-switching was evaluated to determine the con
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centration of zonisamide (ZNS) in human plasma. After the plasma sample was diluted to 10-times with the mobile phase, the sample (101μL) was injected into the column-switching system without pretreatment. ZNS was detected by ultraviolet absorption at 246 nm. The calibration curve of ZNS was linear and ranged from 1.57 to 50μg/mL of plasma. The coefficients of variation in the within-run (n=5) and the between-run (5 days) precisions of ZNS were below 5 %. The limit of quantification was 0.5pg/mL in 1 μL of human plasma. A good correlation was found between the data obtained by this system and the ELISA system using Markit-M Excegran (r=0.956) or the solid-phase-extraction HPLC method (r=0.985). This system for ZNS is thus considered to be a very useful measurement for therapeutic drug monitoring because of its high sensitivity, rapidity and low cost compared with other measurement systems.
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| 20.
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Morisaki, Hiroshi ; Nakamura, Shiho ; Tang, Ning ; Toriba, Akira ; Hayakawa, Kazuichi
概要:
Benzo[c]fluorene (BcFE) concentrations in benzene/ethanol extracts of airborne particulates were determined by high-perf
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ormance liquid chromatography (HPLC) with fluorescence detection. HPLC conditions were as follows: columns, two ZORBAX Eclipse PAH (4.6 i.d. × 250 mm, 3.5 μm) and one Inertsil ODS-P (4.6 i.d. × 250 mm, 5 μm) in series; mobile phase, acetonitrile–water (98:2, v/v), 0.3 mL/min; detection wavelengths, excitation 309 nm, emission 354 nm. Particulate-phase BcFE concentrations in the atmosphere varied seasonally (winter > summer). The concentrations were 11000 ± 6100 pg m−3 (winter) and 40 ± 12 pg m−3 (summer) in Beijing, China, and 13 ± 5.0 pg m−3 (winter) and 2.7 ± 0.52 pg m−3 (summer), in Kanazawa, Japan. In both cities, the particulate-phase BcFE concentration in the atmosphere was lower than that of benzo[a]pyrene (BaP) by a factor of 0.03 – 0.43. However, the mutagenic contribution of particulate-phase BcFE in the atmosphere in winter calculated from the mutagenicity relative potency factor was greater than that of BaP.
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| 21.
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吉崎, 智一 ; Yoshizaki, Tomokazu
概要:
1)核酸アナログタイプ薬剤シドフォビルによるin vitroでの細胞障害性の検討NPC-KT細胞(EBV陽性上皮細胞)による実験を行った。シドフォビルによる細胞障害性は、1mMで0.1mMと比較して明らかに大きかった。2)リボ核酸還元酵素阻
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害剤(RR inhibitor)によるin vitroでの細胞障害性の検討RR inhibitorとして、hydroxyureaおよびdidoxを用いて、同じくNPC-KT細胞に対する細胞障害性を検討した。その結果、hydroxyureaでは濃度が0.125mMを超えると細胞障害性が亢進し、didoxでは0.1mM以上の濃度で細胞障害性が強く出る事が判明した。3)in vitroでの核酸アナログタイプ薬剤およびリボ核酸還元酵素阻害剤の併用による細胞障害性の検討続いて、シドフォビルおよびRR inhibitorを併用した場合、細胞障害性が増強される事が判明した。Hydroxyurea、didoxいずれの場合も、シドフォビルとの相互増強作用は相加的なものであった。さらに、PARP蛋白をウエスターン・ブロット法で同定する事により、細胞障害性の増強にアポトーシスが関与するかどうかについて検討した。シドフォビルおよびRR inhibitorを併用した場合、PARPの分解が進むことから、アポトーシスが関与する事が、判明した。4)in vivoでの核酸アナログタイプ薬剤およびリボ核酸還元酵素阻害剤の併用による細胞障害性の検討ヌードマウスにEBV陽性腫瘍を移植し、上記薬剤を併用した所、腫瘍縮小に少なくとも相加的な効果を認めた。<br />研究課題/領域番号:16659463, 研究期間(年度):2004 – 2006<br />出典：「核酸アナログ系抗ウイルス剤によるウイルス関連腫瘍治療に関する基礎研究」研究成果報告書 課題番号16659463（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-16659463/)を加工して作成
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| 22.
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早川, 和一 ; Hayakawa, Kazuichi
概要:
ディーゼル排出粉塵(DEPE)及びその構成成分の一つである多環芳香族炭化水素(PAH)類の内分泌攪乱作用について,昨年度はエストロゲン様/抗エストロゲン活性を明らかにした.今年度はDEPE及びPAHのアンドロゲン様活性/抗アンドロゲン活性に
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ついて検討した。DEPEをヒトPC3/AR培養細胞を用いたルシフェラーゼレポーターアッセイに適用した結果,アンドロゲン様活性は認められなかったが,抗アンドロゲン活性が観察された。DEPEに含まれるいくつかの4,5環PAHは,強い抗アンドロゲン活性を示した。また,DEPE及び4,5環PAHはいずれも,ヒトのアリルヒドロカーボンレセプター(AhR)のアゴニストであった。以上の結果から,DEPEは抗アンドロゲン活性を示し,その一部はDEPEに含まれるPAHに由来することがわかった。更に,酵母two-hybrid法を用いた結果,DEPE及びいくつかのニトロ多環芳香族炭化水素が抗アンドロゲン活性を示した。次に,分析対象のモノヒドロキシ多環芳香族炭化水素(OHPAH)の数を増加させるために,逆相HPLC/蛍光検出法の条件を改良した。また,ヒト尿試料に適用可能とするために,OHPAHの抱合体も加水分解してOHPAHと合わせて定量する前処理方法を開発した。その結果,喫煙者は非喫煙者に比較して尿中2-ヒドロキシフルオレン濃度が有為に高く,1-ヒドロキシピレンより有効な喫煙指標となることがわかった。また,2〜4環の複数のOHPAHを同時分析した結果,タイ人は日本人に比較して尿中の各種OHPAH濃度が高く,室内で使用する薪燃料由来の煙の影響が大きいと推定された。このように,開発したOHPAH分析法は,ガス状及び粒子状のいずれのPAHの代謝物も分析対象としており,異なる多様なPAH発生源にも対応できることから,ヒトのPAH個人曝露量評価法として有用なことがわかった。<br />Last year, both estrogenic and antiestrogenic actions of diesel exhaust particulate(DEPE) and polycyclic aromatic hydrocarbon(PAH), which was one of the constituent of DEPE, were clarified. This year, both androgenic and antiandrogenic activities of DEPE and PAH were examined. By applying DEPE to the luciferase reporter gene assay in human PC3/AR culture cells, DEPE did not show androgenic activity but antiestrogenic activity. Several PAHs having 4 or 5 rings, which are included in DEPE, showed strong antiandrogenic activity. Both DEPE and PAHs having 4 or 5 rings, were also agonists of human allyl hydrocarbon receptor(AhR). These results suggested that DEPE showed antiandrogenic activity and that a part of this activity was derived from PAHs which were included in DEPE. In addition, several nitropolycyclic aromatic hydrocarbons showed aniandorgenic activity in the yeast two-hybrid assay. Next, to increase the number of monohydroxy polycyelic aromatic hydrocarbons(OHPAH) as analytes, conditions of our HPLC/fluorimetric detection method were modified. And, to anayze both urinary OHPAHs and their conjugates, the pretreatment method including hydrolysis of the conjugates was developed. As the result, the urinary concentration of 2-hydroxyfluorene in smokers' urine samples was higher than that in nonsmokers', and it was proven that 2-hydroxyfluorene was a more effective biomarker for smoking than 1-hydroxypyrene. Urinary OHPAH concentrations of Thai subjects were higher than those of Japanese. As a possible reason for this, the smoke of the firewood fuel used in the indoor of Thai house was considered.<br />研究課題/領域番号:14370728, 研究期間(年度):2002–2003<br />出典：「多環芳香族炭化水素とその代謝物の内分泌撹乱作用とその測定法に関する研究」研究成果報告書 課題番号14370728 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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論文
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早川, 和一 ; Hayakawa, Kazuichi
概要:
(1)大気粉じんから変異原物質を抽出するために使用されている様々な有機溶媒の中から,ニトロアレーン分析法とAmes法の併用に最適な抽出溶媒の検索をおこなった.1,3-, 1,6-, 1,8-ジニトロピレン(DNP),1-ニトロピレン(NP)
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及び直接変異原性物質の抽出効率はベンゼン-エタノール(3:1),アセトニトリル,エタノール,メタノールの順で高く,毒性を考慮するとこれらの中ではエタノールが最も適していると考えられた. (2)基本ニトロアレーン分析計では試料の前処理として必要な還元操作を,分析システムに亜鉛を充填した還元用カラムを導入することにより省略した.また,分離度を向上させるため,試料を還元後,最も還元成績体の濃度が高い部分をスイッチングバルブでハードカッティングして,分析カラムに導入した.これによって簡単な前処理のみで大気粉じん中の1,3-, 1,6-, 1,8-DNP及び1-NPが定量可能となった. (3)ニトロアレーン分析法の前処理操作では直接変異原性ニトロアレーンと同時に間接変異原性多環芳香族炭化水素(PAH)も定量化に抽出される.この試料をニトロアレーン分析計とPAH分析のための蛍光検出HPLCシステムをスイッチングバルブで併合したシステムに適用することで,両者の同時分析が可能となった.その結果,上記の4種ニトロアレーンに加えて8種PAHも1時間以内に定量可能となった. (4)大気中で2次生成することが知られている2-, 4-NP,2-ニトロフルオランテン,6-ニトロクリセンと1-NPを同時に分析するため,基本ニトロアレーン分析システムに妨害物質を除去するための精製用ODSカラム,還元を自動化する亜鉛充填カラムと分離・検出を改善する濃縮用ODSカラムを導入した.本法によって測定した金沢市市街地大気中の上記化合物濃度は10^<-12>-10^<-16>molm^<-3>の範囲にあった.<br />(1) Both the nitroarene analyzer and the Ames test are necessary in the study on mutagenic nitroarenes. For the simultaneous use of these two methods, several solvent systems were tested to extract 1,3-dinitropyrene (1,3-DNP), 1,6-DNP,1,8-DNP and 1-nitropyrene (1-NP) as well as directacting mutagenic activity from airborne particulates. Benzene-ethanol, acetonitrile, ethanol and methanol gave the high efficiencies. Considering toxicities, ethanol seemed to be the best solvent.(2) Although the nitroarene analyzer determined trace levels of 1,3-, 1,6-and 1,8-DNPs and 1-NP in extracts from a few mg of airborne particulates, the reduction of nitroarenes to corresponding aminoarenes was required before injection. To remove this tedious treatment, a reducer column packed with zinc/glass beads was on-line introduced into the system. Considering the better resolution of aminoarenes, both the reducer column and a switching valve equipped with a heart-cutting loop were introduced just before the ODS separation column. This system could determine the above four compounds in extracts from airborne particulatates without pre-column reduction.(3) In the method, not only nitroarenes but also polycyclic aromatic hydrocarbons (PAHs) were quantitatively extracted from airborne partculates. To determine them simultaneously, both the nitroarene analyzer and a conventional high-performance liquid chromatograph with a fluorescence detector were combined using a switching valve. After the reduced sample solution was injected, four nitroarenes and eight PAHs were separately determined in the two different lines in 1h with high sensitivities.(4) Several mutagenic nitroarenes such as 2-, 4-NPs, 2-nitrofluoranthene and 6-nitrochrycene were formed in air in the presence of NOx. To determine these compounds, a reducer column packed with zinc/glass beads and two ODS columns, one for the clean-up and the other for the concentration, were introduced into the nitroarene analyzer. By the system, the above four compounds were detected in air. The fact that their ratios to 1,3-, 1,6-, 1,8-DNPs and 1-NP in rural air were larger than those in urban air suggested the formation of those compounds during the transportation. However, their mutagenic contributions were not large.<br />研究課題/領域番号:06557121, 研究期間(年度):1994–1995<br />出典：「ニトロアレーン分析計の試作」研究成果報告書 課題番号06557121(KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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