The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 25 , Issue 1
Showing 1-12 articles out of 12 articles from the selected issue
  • Hiroshi NAKATA, Fumio SAGAMI, Toru HORIE
    2000 Volume 25 Issue 1 Pages 1-10
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Following single-dose intravenous and oral studies to determine the absolute bioavailability of E5110 in beagle dogs, repeated dose pharmacokinetic studies were conducted as toxicokinetics in a subacute toxicity test. E5110 was administered orally once a day for 91 days at doses of 0, 1, 10, 50 and 250 mg / kg / day to dogs.On the first day during repeated administration, the Cmax and AUC values of E5110 in females were lower than those for males, and it seems that this may be due to a sex-related difference in the activity of cytochrome P450(CYP)3A. During repeated administration of E5110, the plasma levels of E5110 on day 15 and day 91 were markedly lower than those on the first day. On day 91, the AUCs for E5110 were 55.9%, 38.8%, 10.9% and 7.8% in males, and 76.2%, 80.3%, 10.5% and 11.9% in females on the first day, for doses of 1, 10, 50 and 250 mg / kg / day, respectively.Liver microsomes prepared after the last dose of E5110 showed increased activities of benzphetamine N-demethylase, p-nitroanisole O-demethylase, and aminopyrine N-demethylase, at doses of 1 mg / kg / day or more. A dose-dependent increase in P450 content was also observed. Furthermore, the capacity for 5-hydroxylate E5110 was increased, and Western blot analysis indicated an induction of CYP2B and 3A;therefore CYP3A may contribute to a main metabolic pathway of E5110.These results suggested that the decrease in plasma concentrations of E5110 that were observed during repeated administration represents a typical case of auto-induction of the phenobarbital type.
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  • Tomoko HARADA, Katsumi TAKABA, Takuji HARA, Noboru YAMAMOTO, Tomohide ...
    2000 Volume 25 Issue 1 Pages 11-15
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    An animal model for testing pulmonary toxicity of KW-2149, a new mitomycin C analogue, was developed(by intravenously injecting 3.28 mg / kg of the drug in to male SD rats 3 times at weekly intervals), and exhibits pleural effusion from 1 week after the last injection. In this animal model, repeated intravenous injections of dexamethasone(DM), following any of three different schedules examined, were more or less effective of reducing the amount of effusion. The optimal results were obtained with 4 administrations a week(i. e. twice before and twice after KW-2149 treatment). The results of the present experiment suggest possible clinical application of DM in protecting patients from pulmonary toxicity of KW-2149.
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  • Masaaki MORI, Hiroshi KOBAYASHI, Masako NAGANUMA, Chiyomi SUGIYAMA, Yo ...
    2000 Volume 25 Issue 1 Pages 17-24
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The activity of ultraviolet(UV)light to induce unscheduled DNA synthesis(UDS)was investigated in hairless mouse epidermis by means of an in vivo-in vitro assay using a liquid scintillation counting method. Groups of three to five 8-week-old female hairless mice were irradiated with UV-B or UV-A, then skin samples were taken and cultured individually in medium containing[3H]thymidine with or without hydroxyurea(HU)for 2 hr. DNA of the epidermis was extracted, and incorporation of[3H]thymidine and the DNA content were determined with a liquid scintillation counter and a fluorescence spectrophotometer, respectively. Induction of UDS was judged in terms of the UDS index[(the ratio of DNA synthesis in the presence of HU to that in its absence)×100]. UV-B increased the UDS index 1 hr after irradiation of 500 J / m2, which corresponds to approximately 1 minimal erythema dose or 1 minimal edema dose, and showed a dose-dependent increase up to 17-fold in the UDS index at irradiation doses of 500 to 2, 000 J / m2. In a time-coures study, UV-B also increased replicative DNA synthesis(RDS)48 hr after irradiation at 1, 000 J / m2. On the other hand, UV-A did not increase the UDS index at irradiation doses of 2×105 to 8×105 J / m2. These results show that induction of UDS by UV irradiation depends on wavelength, and an increase of RDS in the epidermis exposed to UV-B irradiation appears after induction of UDS.
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  • Hironori TAKAGI, Akinori SATOH, Rika SHIRANE, Tomonori HASHIMOTO, Tada ...
    2000 Volume 25 Issue 1 Pages 25-31
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Ethyl methanesulfonate(EMS), an alkylating agent which induces dominant lethals, was administered in oral doses of 100 mg / kg to Crj:CD(SD)IGS male rats for 5 consecutive days. At the termination of treatment and after a 28-day withdrawal, mating with untreated females and sperm analysys(motion, number, and morphology)were performed. The copulated females were sacrificed at 20 days of gestation.At the termination of treatment, no clinical signs related to EMS were observed except for a decrease in body weight. Gross pathology and sperm analysis revealed no abnormalities in treated males. However, females mated at the termination of treatment had a clearly higher fetal mortality.Females mated after the 28-day withdrawal exhibited lower fetal mortality than females mated at the termination of treatment. On the other hand, females mated after the 28-day withdrawal exhibited a lower implantation rate that was not observed in females mated at the termination of treatment. For males after a 28-day withdrawal, sperm analysis revealed both a decrease in sperm motion and number and an increase in morphological change.These findings indicate that two types of male reproductive toxicity induced by EMS can be distinguished. One induces a low implantation rate that can be detected by sperm analysis, while the other induces fetal lethals that could not be detected by sperm analysis in this study.
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  • Makoto SEKI, kikuko KASAMA, Kiyoshi IMAI
    2000 Volume 25 Issue 1 Pages 33-40
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Five-week-old Sprague-Dawley rats of both sexes were assigned to two types of feeding condition. One was fed ad libitum(AL)on commercial chow and another was fed a restricted amount of the chow(FR), approximately 75% of that fed in the AL condition. In each feeding condition, animals were orally administered carbon tetrachloride (CCl4) at levels of 0(control), 0.1 or 0.2 ml / kg 6 days a week for 8 weeks. Lesions of the liver(hepatic cellular degeneration and fibrosis)and of the kidney(proximal tubular vacuolation and glomerular sclerosis)induced by CCl4 were aggravated in the FR group. The FR-control showed a higher metabolic activity of aniline in the liver than the AL-control group. Plasma lipid-peroxide(LPO)level was higher in the AL-control group than in the FR-control group. With CCl4 0.2 ml / kg treatment however, the plasma LPO level was reversed between the AL and the FR groups. Taking together these somewhat unexpected results, it was concluded that(1)25%food restriction increases toxicity of repeatedly administered CCl4 in rats, and(2)aggravation of CCl4 toxicity may be partly due to enhanced metabolic activation of CCl4 resulting from food restriction.
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  • Toshinobu YAMAMOTO, Mitsuru YONEYAMA, Masanori IMANISHI, Masaki TAKEUC ...
    2000 Volume 25 Issue 1 Pages 41-48
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Flow cytometric analysis has been developed to detect tailless sperm with heads detached from the tails at the neck position. When isolated tailless sperm suspension was subjected to flow cytometry, a second sperm population appeared alongside the normal sperm population on light scatter-histogram. The percentage of this second sperm population(85.2%)was in good agreement with that for the tailless sperm(88.7%)determined microscopically, indicating that the second sperm population would correspond to tailless sperm population in the light scatter-histogram. Rates for tailless sperm determined by flow cytometry significantly correlated with those estimated microscopically following exposure of sperm to either sonication(r=0.94, P<0.01), or nitrobenzene(r=0.80, P<0.01). The results indicated the utility of the light scatter-histogram in flow cytometry as a simple and convenient procedure for the detection of tailless sperm induced by chemical compounds.
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  • Masami SUZUKI, Minoru MACHIDA, Kenji ADACHI, Kouji OTABE, Tetsuro SUGI ...
    2000 Volume 25 Issue 1 Pages 49-55
    Published: February 28, 2000
    Released: February 21, 2008
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    Pulmonary drug administration of most peptide / protein drugs is characterized by low bioavailability due to low permeability. Surface active agents have been tested as an absorption enhancer, but few studies have been carried out on the local toxicity of these additives. In the present study, to clarify the toxic effects of surface active agents on the lung, a relatively high concentration(1%)of polyoxyethylene 9 lauryl ether(Laureth-9)and sodium glycocholate(SGC)was given to rats in a single intratracheal instillation(100μl / rat), and the lung was evaluated histopathologically, In the rats treated with Laureth-9, lung lesions were observed in the bronchi to alveoli. At 1 day after administration, edema, hemorrhage and inflammatory cell infiltration due to degeneration and desquamation of from the lung injury, such as hyperplasia of epithelium and sporadic fibrosis, was noted. SGC also induced lung lesions with a similar histopathological nature, whereas the lesions were mostly confined to the alveoli. These results suggest that surface active agents induce acute inflammation of the lung by intratracheal instillation, that the distribution of lesions is different among surface active agents, and moreover that pathological examination is indispensable for clarifying local toxicity of absorption enhancers in pulmonary drug-delivery studies.
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  • Satoshi NUMAZAWA, Masakatsu SHIBATA, Susumu IMAOKA, Yoshihiko FUNAE, T ...
    2000 Volume 25 Issue 1 Pages 57-61
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratogenic compound cis-1-[-4-(p-menthane-8-yloxy)phenyl]piperadine (YM9429)selectively induces skeletal malformations characterized by cleft palate in rat fetuses. In the present study, we investigated the effect of YM9429 on hepatic cytochrome P-450s and their activities in rats. Oral administrations of YM9429 at a dose of 250, 500 or 750 mg / kg daily for 3 days induced cytochrome P-450 contents in a dose-dependent manner. Concomitant induction of enzyme activities of benzphetamine N-demethylase, erythromycin N-demethylase and, to a lesser extent, aminopyrine N-demethylase was observed. Immunoblot analysis revealed that YM9429 up-regulated hepatic levels of CYP2B1 / 2 and CYP3A1 / 2 proteins. A single dose of YM9429 at 250 mg / kg induced CYP2B1 / 2 protein levels significantly. These results suggest that YM9429 is a strong inducer of cytochrome P-450 with characteristics resembling those of phenobarbital.
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  • [in Japanese]
    2000 Volume 25 Issue 1 Pages App11-App19
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • [in Japanese], [in Japanese]
    2000 Volume 25 Issue 1 Pages App21-App26
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • [in Japanese]
    2000 Volume 25 Issue 1 Pages App33-App38
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • [in Japanese], [in Japanese]
    2000 Volume 25 Issue 1 Pages App39-App44
    Published: February 28, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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