The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Current issue
Displaying 1-4 of 4 articles from this issue
Original Article
  • Tomoaki Tochitani, Yasuhiro Sasaki, Naoe Nishimura, Yuta Fujii, Takayu ...
    2022 Volume 47 Issue 7 Pages 269-276
    Published: 2022
    Released on J-STAGE: July 01, 2022
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    Supplementary material

    Microsampling (MS) has been increasingly used in toxicity studies reducing animal use for toxicokinetic analysis. However, especially for drugs with hematotoxic properties, the potential effects of MS on hematological parameters and subsequent toxicity assessment should be considered, while such properties are frequently unknown at the discovery stage. Here, we conducted a rat 2-week study of hematotoxic compounds and evaluated the effects of MS on toxicity assessment. Six-week-old female SD rats were orally dosed with vehicle, methylene blue trihydrate (MB: 300 mg/kg/day), or azathioprine (AZP: 12 and 24 mg/kg/day) for 2 weeks. Each treatment group was divided into non-MS and MS subgroups, and in the MS subgroups, 50 μL/time point of blood was collected from the jugular vein at 7 time points each on Days 1 and 13 of dosing. The test items included clinical signs, body weight, urinalysis, hematology, blood chemistry, necropsy, organ weight, and histopathology. In the MB non-MS subgroup, there were low values in red blood cell parameters, high values in reticulocytes and bilirubin, and increased extramedullary hematopoiesis, reflecting hemolytic anemia. In the AZP non-MS subgroup, there were low values of red and white blood cell parameters and decreased cellularity in the bone marrow, reflecting myelosuppression. The effects of MB and AZP were similarly observed in the MS subgroups, and the effects of MS on the toxicological endpoints were generally small. Based on these results, the effects of MS on toxicity assessment were considered to be small in rat toxicity studies even for hematotoxic compounds.

Original Article
  • Koya Sato, Seigo Sanoh, Yuji Ishida, Chise Tateno, Shigeru Ohta, Yaich ...
    2022 Volume 47 Issue 7 Pages 277-288
    Published: 2022
    Released on J-STAGE: July 01, 2022
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    Felbamate (FBM) is an antiepileptic drug that has minimal toxicity in preclinical toxicological species but has a serious idiosyncratic drug toxicity (IDT) in humans. The formation of reactive metabolites is common among most drugs associated with IDT, and 2-phenylpropenal (2-PP) is believed to be the cause of IDT by FBM. It is important to consider the species difference in susceptibility to IDT between experimental animals and humans. In the present study, we used an in vitro and in vivo model system to reveal species difference in IDT of FBM. Human cytochrome P450 (CYP) and carboxylesterase (CES) expressing microsomes were used to clarify the isozymes involved in the metabolism of FBM. The remaining amount of FBM was significantly reduced in incubation with microsomes expressing human CYP2C8, 2C9, 2E1, and CES1c isozymes. Chimeric mice with humanized liver are expected to predict IDT in humans. Therefore, metabolite profiles in chimeric mice with humanized liver were investigated after administration of FBM. Metabolites after glutathione (GSH) conjugation of 2-phenylpropenal (2-PP), which is the reactive metabolite responsible for FBM-induced IDT, were detected in chimeric mice plasma and liver homogenate. Mass spectrometry imaging (MSI) visualizes distribution of FBM and endogenous GSH, and GSH levels in human hepatocyte were decreased after administration of FBM. In this study, we identified CYP and CES isozymes involved in the metabolism of FBM and confirmed reactive metabolite formation and subsequent decrease in GSH using humanized animal model. These results would provide useful information for the susceptibility to IDT between experimental animals and humans.

Original Article
  • Ryo Ichikawa, Sosuke Masuda, Junta Nakahara, Mio Kobayashi, Risako Yam ...
    2022 Volume 47 Issue 7 Pages 289-300
    Published: 2022
    Released on J-STAGE: July 01, 2022
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    Supplementary material

    To study the effects of autophagy inducer carbamazepine (CBZ) in a high-fat diet (HFD)/streptozotocin (STZ)-related early hepatocarcinogenesis model, we determined autophagic flux by immunohistochemical analysis of autophagy marker expression in preneoplastic liver foci and compared that with the expression of the NADPH oxidase subunit. Male F344 rats were fed a basal diet or HFD and subjected to two-stage hepatocarcinogenesis; diabetes mellitus was induced via STZ administration. Several STZ-treated, HFD-fed rats were administered CBZ (a total of five doses every one or two days) at week 7 and 8. STZ-treated, HFD-fed rats decreased β cells in the islet of Langerhans and increased adipophilin-positive lipid droplets in the liver; moreover, they had a larger area of glutathione S-transferase placental form-immunopositive preneoplastic liver foci, which was associated with inhibition of autophagy and induction of the NADPH oxidase subunit, as demonstrated by increased immunohistochemical expression of an autophagosome receptor marker microtubule-associated protein light chain 3 (LC3)-binding protein p62, and of an NADPH oxidase subunit p22phox in the preneoplastic foci. An increased trend of an autophagy phagophore marker LC3 in preneoplastic foci was also detected. CBZ administration could induce autophagy and impair p22phox expression, as shown by altered expression of autophagy regulators (Atg5, Atg6, Lamp1, Lamp2, and Lc3), NADPH oxidase subunits (P22phox and P67phox), and antioxidant enzymes Gpx1 and Gpx2. These results suggest that inhibition of autophagy and induction of p22phox might contribute to HFD/STZ-related early hepatocarcinogenesis in rats; however, the effects of CBZ administration on the STZ/HFD-increased preneoplastic foci were marginal in this study.

Original Article
  • Ikuro Takakura, Tomoyuki Kishida, Ryohei Yokoi, Shinji Souma
    2022 Volume 47 Issue 7 Pages 301-308
    Published: 2022
    Released on J-STAGE: July 01, 2022
    JOURNAL FREE ACCESS FULL-TEXT HTML

    We examined that an estradiol-dominant state against progesterone could affect hematological parameters through hemodilution because estradiol is known to increase plasma volume via oncotic pressure. We performed a 2- and 3-week repeated oral dose study with mifepristone, a progesterone receptor antagonist, in female rats and examined erythrocyte counts, hemoglobin, hematocrit, plasma volume, levels of estradiol and progesterone, water intake, and water loss. Mifepristone treatment decreased some hematological parameters mildly and increased plasma volume. There were no remarkable changes in the balance of water intake and water loss through urination. Both estradiol and progesterone levels and the ratio of estradiol to progesterone increased. Therefore, our findings indicate that repeated mifepristone treatment increases estradiol levels and plasma volume, resulting in lower erythrocyte counts, hemoglobin, and hematocrit. The present study proved the possible contribution of estradiol to understanding the toxicological significance of mifepristone-induced hemodilution.

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