The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
Search
OR
Browse
Search
Current issue
Showing 1-5 articles out of 5 articles from the selected issue
    • |<
    • <
    • 1
    • >
    • >|
Original Article
  • Shugo Suzuki, Hiroyuki Kato, Satoshi Fuji, Taku Naiki, Aya Naiki-Ito, ...
    Volume 43 (2018) Issue 6 Pages 359-367
    Released: June 05, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Screening prostatic carcinogens is time-consuming due to the time needed to induce preneoplastic and neoplastic lesions. To overcome this, we investigated alternative molecular markers for detection of prostatic carcinogens in a short period in rats. After treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), expression of high-mobility group protein B2 (HMGB2) was up-regulated in rat ventral prostate. To evaluate the applicability of HMGB2 in the early detection of carcinogenicity of chemicals using animal models, we examined HMGB2 expression in prostate of rats. Six-week-old male F344 rats were gavaged for four weeks with a total of eight individual chemicals, divided into two categories based on prostate carcinogenicity. Animals were sacrificed at the end of the study and HMGB2 immunohistochemistry was performed. HMGB2 expression in least one prostate lobe was significantly increased by all four prostate carcinogens compared with the controls. In contrast, the four chemicals that were not carcinogenic in the prostate did not cause HMGB2 up-regulation. Additionally, high HMGB2 expression in neoplastic lesions in both rat and human was detected. Therefore HMGB2 expression may be a good screening tool for the identification of potential of prostate carcinogens.

    View full abstract
Original Article
  • Norie Murayama, Hiroshi Suemizu, Shotaro Uehara, Takashi Kusama, Marin ...
    Volume 43 (2018) Issue 6 Pages 369-375
    Released: June 05, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity—attributable to drug metabolism and disposition, but having immunomodulatory properties—is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 hr after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.

    View full abstract
Original Article
  • Weiwei Huang, Juan Chang, Ping Wang, Chaoqi Liu, Qingqiang Yin, Qun Zh ...
    Volume 43 (2018) Issue 6 Pages 377-385
    Released: June 05, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Aflatoxin B1 (AFB1) and zearalenone (ZEA) are the secondary toxic metabolites of fungi which contaminate a wide range of food and feedstuffs. Limiting exposure of humans and livestock to them is very essential. Among numerous methods of mycotoxin-degradation, biodegradation by microorganisms and enzymes is an effective and promising approach to eliminate their hazards. The present study aims to optimize the proportion of different species of beneficial microbes by means of response surface methodology (RSM) and its combination with mycotoxin-degradation enzymes. The results indicated that AFB1 and ZEA degradation rates were 38.38% and 42.18% by individual Bacillus subtilis (P < 0.05); however, AFB1 and ZEA degradation rates reached 45.49% and 44.90% (P < 0.05) when three probiotic species such as Bacillus subtilis, Lactobacillus casein and Candida utilis were at a ratio of 1:1:1, corresponding with the predictive value of the RSM model. The further experiment showed that AFB1 and ZEA degradation rates were 63.95% and 73.51% (P < 0.05) when the compound of three probiotic species was combined with mycotoxin-degradation enzymes from Aspergillus oryzae at a ratio of 3:2. This result indicated that the combination of probiotics with mycotoxin-degradation enzymes is a promising new approach for synchronous detoxification of AFB1 and ZEA.

    View full abstract
Letter
  • Makiko Shimizu, Hiroshi Suemizu, Sawa Mizuno, Takashi Kusama, Tomonori ...
    Volume 43 (2018) Issue 6 Pages 387-393
    Released: June 05, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Medicinal carnitine-derived and dietary-derived malodorous trimethylamine and its non-malodorous metabolite trimethylamine N-oxide were historically regarded as nontoxic. Clinical and toxicological interest has recently arisen because of their potential association with atherosclerosis. We previously reported a human physiologically based pharmacokinetic (PBPK) model for trimethylamine and its primary metabolite, trimethylamine N-oxide, based on reported rat trimethylamine pharmacokinetics. However, rats are poor metabolizers with respect to trimethylamine N-oxygenation, and this species difference was investigated in vitro using substrate depletion rates in rat and human liver microsomes. The current study investigated the pharmacokinetics of deuterium-labeled trimethylamine orally administered to immunodeficient humanized-liver mice transplanted with commercially available human hepatocytes. Trimethylamine N-oxide was extensively formed in vivo in humanized-liver mice, but not in control mice. The experimental pharmacokinetic data of deuterium-labeled trimethylamine and its N-oxide in humanized-liver mice were scaled up for application to a human PBPK model. The human plasma concentration curves generated by the resulting simple PBPK model were consistent with concentrations in humans reported in the literature. The model can also simulate human plasma levels of trimethylamine and trimethylamine N-oxide during treatment with the prescription medicine L-carnitine and in trimethylamine loading tests. The predicted plasma levels were in the ranges that occur under the consumption of daily dietary foodstuff; such levels are associated with few toxicological impacts. The present PBPK model for trimethylamine and trimethylamine N-oxide could estimate daily doses by both forward and reverse dosimetry and could facilitate risk assessment in humans.

    View full abstract
Original Article
  • Keisuke Goda, Kosuke Saito, Kyotaka Muta, Akio Kobayashi, Yoshiro Sait ...
    Volume 43 (2018) Issue 6 Pages 395-405
    Released: June 05, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Valproic acid (VPA) is known to induce hepatic steatosis due to mitochondrial toxicity in rodents and humans. In the present study, we administered VPA to SD rats for 3 or 14 days at 250 and 500 mg/kg and then performed lipidomics analysis to reveal VPA-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. VPA induced hepatic steatosis at the high dose level without any degenerative changes in the liver on day 4 (after 3 days dosing) and at the low dose level on day 15 (after 14 days dosing). We compared the plasma and hepatic lipid profiles obtained on day 4 between the VPA-treated and control rats using a multivariate analysis to determine differences between the two groups. In total, 36 species of plasma lipids and 24 species of hepatic lipids were identified as altered in the VPA-treated group. Of these lipid species, ether-phosphatidylcholines (ePCs), including PC(16:0e/22:4) and PC(16:0e/22:6), were decreased in both the plasma and liver from the low dose level on day 4, however, neither an increase in hepatic TG level nor histopathological hepatic steatosis was observed at either dose level on day 4. Hepatic mRNA levels of glycerone-phosphate O-acyltransferase (Gnpat), which is a key enzyme for biosynthesis of ePC, was also decreased by treatment with VPA along with the decrease in ePCs. In conclusion, the changes in ePCs, (PC[16:0e/22:4] and PC[16:0e/22:6]), have potential utility as predictive biomarkers for VPA-induced hepatic steatosis.

    View full abstract
    • |<
    • <
    • 1
    • >
    • >|
feedback
Top