The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 22 , Issue 1
Showing 1-7 articles out of 7 articles from the selected issue
  • Akitaka MATSUDA, Kazuhiro HIGUCHI, Michiyo KARASAWA, Shigeki YONEYAMA, ...
    1997 Volume 22 Issue 1 Pages 1-24
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    CGS 16949A, an aromatase inhibitor, was administered orally to female rats at doses of 1 and 10 mg/kg/day alone and in combination with tamoxifen (0.5 or 5mg/kg/day) or 5-fluorouracil (20 mg-g/day) for 14 days. CGS 16949A and tamoxifen combination: Increased food intake and body weight noted after CGS 16949A treatment were also observed following combination treatment, though to a lesser degree. Most of the clinical pathological features noted following combination treatment were similar to those induced by single compound treatment. Gross pathological and histopathological changes ascribed to the antiestrogenic action of CGS 16949A, such as increased ovarian weight, decreased uterine weight, cystic follicles and atrophied uterus and vaginal epithelium, were alleviated by combination treatment, and were comparable in severity to those caused by tamoxifen alone. No severe toxic changes were induced by combination treatment. CGS 16949A and 5-fluorouracil combination: Increased body weight noted after CGS 16949A treatment was also observed following combination treatment, though to a lesser degree. Most of the changes caused by single compound treatment, including the aforementioned effects of CGS 16949A on the genital organs, were also noted following combination treatment. There was no evidence of enhancement of the effects by combination treatment.
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  • Toshiaki MATSUZAWA, Yutaka HAYASHI, Mamoru NOMURA, Takashi UNNO, Toshi ...
    1997 Volume 22 Issue 1 Pages 25-44
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A control survey was conducted to check the accuracy of automated analyzers used in the evaluation of clinical chemistry parameters in nonclinical toxicology studies. Pooled serum samples from male Sprague-Dawley rats were delivered refrigerated to each facility 98 laboratory facilities throughout Japan within 18 hours after sample preparation and analyzed. Commercially available normal human serum samples from a single lot were also analyzed at the same time. Survey results were divided into three categories. (1) Parameters with small coefficient of variation (CV) values for both rat and human serum samples included protein, glucose, cholesterol (CHO), urea nitrogen (UN), sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and inorganic phosphate (IP). Definition of normal values in rats should be straight forward for these parameters. (2) Parameters with large CV values, but with a relatively good correlation between rat and human values include triglycerides (TG), glutamic oxaloacetic transaminase/aspartate aminotransferase (GOT/AST), glutamic pyruvic transaminase/alanine aminotransferase (GPT/ALT), and alkaline phosphatase (ALP). Measurements based on different principles gave different mean values, and this values contributed to the increase in CV values. Assessment of normal values would require a consideration of the measurement principles. (3) Parameters with large CV values only in rat serum samples included albumin (albumin/globulin ratio: NG ratio), creatinine (CRE), and total bilirubin (BIL). Reactivity was different in rat albumin (ALB), depending on the reagents used. This difference needs to be corrected with values available by electrophoresis, or adjusted by rat ALB value3, because of the lack of an appropriate measurement method. The enzyme method gave low values for rat CRE, which suggests the need for further examination of this method. The BIL values were extremely low in rat samples. It seems to be necessary to select appropriate methods to measure clinical pathology parameters correctly for rats. There was no deviation in values due solely to the mechanical operations of the analytical equipment. Non-standard initial settings of the equipment (equipment originally intended for human samples, but now applied to animal samples) was the main cause of the wide range of analytical values seen.
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  • Kunio ITOH, Kaori NAKAMURA, Teruyuki KIMURA, Susumu ITOH, Tetsuya KAMA ...
    1997 Volume 22 Issue 1 Pages 45-56
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A mouse liver cDNA clone, MFMO1, coding for a flavin-containing monooxygenase (FMO) was isolated. This cDNA clone encoded a protein of 532 amino acids. Based upon its predicted amino acid sequence, this clone was assumed to belong to the FMO1 subfamily. The deduced amino acid sequence showed 94, 84, 83, and 83% identity with FMO1s of rats, pigs, rabbits and humans, respectively, while it showed only 50-59% identity with human FMO3 and FMO4, rabbit FMO2, FMO3, FMO4 and FMO5, and guinea-pig FMO2. RNA blot analysis showed that the mouse FMO1 was also expressed in the lung and kidney and to lesser extents in the heart, spleen, testis and brain. Mouse FMO1 expressed in yeast showed activities of thiobenzamide S-oxidation, and NADPH oxidation associated with the S- or N-oxidation of chlorpromazine, N, N-dimethylaniline, N, N-dimethyl-hydrazine, imipramine, nicotine, thioacetamide, thiourea and trimethylamine. Moreover, 1, 2, 3, 4-tetrahydroisoquinoline (TIQ), a substance known to induce a parkinsonism-like syndrome in monkeys, was also metabolized by the mouse FMO1. The Km values for chlorpromazine, imipramine and TIQ were determined to be 2.4, 16.0, 435 mM, respectively. This is the first report to show that an expressed FMO can metabolize a neurotoxin, TIQ.
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  • Mizue MAKIMURA, Miho IWAI, Hideya SUGIMOTO, Hideomi FUKUDA
    1997 Volume 22 Issue 1 Pages 57-64
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    In a previous study we indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor in the development of morphine dependence as assessed by naloxone-induced rise in norepinephrine release in chronically morphine-treated rats. In the present experiments, we studied (1) the possible role of protein kinases in the increased norepinephrine release occurring after naloxone injection and (2) the effects of NMDA receptor antagonists on chronic morphine exposure-induced changes in protein kinase activity. The naloxone-induced rise in norepinephrine release was attenuated by concomitant administration of a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7) or an NMDA receptor antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a, d]-cyclohepten-5, 10-imine hydrogen maleate (dizocilpine, MK-801) with morphine. Both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), which mediate neurotransmitter release, were clearly activated in the cytosol of the pons/medulla, but not in that of the hippocampus, in chronically morphine-treated rats. This activation of PKA and PKC by chronic morphine treatment was inhibited by infusion of dizocilpine or D(-)-2-amino-5-phosphonopentanoic acid (AP-5), an ionotropic glutamate receptor antagonist, together with morphine. These results suggest that NMDA receptor antagonists inhibit the increase in protein kinase activity produced by chronic morphine treatment, thus suppressing the naloxone-induced rise in norepinephrine release.
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  • Hideyuki YAMADA, Sachiko SHIIYAMA, Toyomi SOEJIMAOHKUMA, Shin-ichiro H ...
    1997 Volume 22 Issue 1 Pages 65-73
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Deamination or oxidative cleavage of the carbon-nitrogen bond in various phenylisopropylamines was examined in liver microsomes from rabbits and rats, and in reconstituted systems containing CYP2C subfamily isozymes. Kinetic studies of phenylacetone formation from six amphetamine (AP) derivatives, catalyzed by rabbit liver microsomes, indicated that AP had the highest apparent affinity (lowest Km) and increasing the size of the substituent on the nitrogen atom decreased the affinity. The values of maximal velocity increased with increasing size of the substituent. Experiments with purified CYP2C3 from rabbit liver gave similar results: this enzyme showed the highest activity for phenylacetone formation from benzphetamine (BZP) and showed lower activities with compounds having smaller nitrogen substituents. Based on these results, we conclude that among a series of AP derivatives, the parent phenylisopropylamine has the highest affinity for rabbit liver deaminase, where as BZP has the highest turnover. However, the intrinsic clearance (Vmax/Km) values for the individual reactions tended to be comparable. The rates of BZP and deprenyl N-demethylation by rat CYP2C11 and 2C13 were far greater than those of the reactions at other N-α-positions. This result indicated that rat CYP2C enzymes have a more rigid regioselectivity than rabbit CYP2C3 for the deamination/N-dealkylation of phenylisopropylamines.
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  • [in Japanese]
    1997 Volume 22 Issue 1 Pages App27-App34
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • [in Japanese]
    1997 Volume 22 Issue 1 Pages App35-App43
    Published: February 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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