著者

Satoshi Tamai Takuma Iguchi Noriyo Niino Kei Mikamoto Ken Sakurai Ayako Sayama Hitomi Shimoda Wataru Takasaki Kazuhiko Mori

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.42, no.1, pp.73-84, 2017-02-01 (Released:2017-01-07)

参考文献数

44

被引用文献数

6 8

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Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

著者

Mai Nishikawa Naoki Ohara Yukiko Naito Chihiro Amma Yoshiaki Saito Kenjiro Tatematsu Jinhua Baoyindugurong Daisuke Miyazawa Yoko Hashimoto Harumi Okuyama

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.9, no.1, pp.7-16, 2022 (Released:2022-01-15)

参考文献数

30

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The present study was conducted to survey the influence of canola oil (CAN) ingestion on the steroid hormone production in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP were fed a diet containing 10 wt/wt% soybean oil (SOY, the control) or CAN as the sole dietary fat for 8 weeks. Plasma concentration of luteinizing hormone (LH) was similar in the 2 dietary groups. However, the plasma testosterone level in the CAN group, 1.36 ± 0.271 ng/mL, was lower than in the SOY group, 2.79 ± 0.514 ng/mL (p < 0.05, unpaired t-test; n = 10), and plasma concentration of aldosterone in the CAN group, 345 ± 79.6 pg/mL, was higher than in the SOY group, 159 ± 33.7 pg/mL (p < 0.05, unpaired t-test; n = 10). In the testis, the expressions of mRNA for StAR, CYP11A1, CYP17, 3βHSD and 17βHSD and the amounts of the corresponding proteins were significantly decreased. However, in the adrenal gland, the expressions of mRNA for StAR, CYP11A1, 3βHSD and CYP11B1 in the CAN group were not different from those in the SOY group, but the expression of mRNA and the amount of the corresponding protein for CYP11B2 were increased significantly in the CAN group. These findings are indicative of a peripheral, testicular toxicity of CAN. The decreased testosterone and the concomitantly increased aldosterone may play a role in the aggravation by CAN of the genetic diseases (i.e., metabolic syndrome-like complications) in male SHRSP.

著者

Ryo Ichikawa Sosuke Masuda Junta Nakahara Mio Kobayashi Risako Yamashita Suzuka Uomoto Ohshima Kanami Erika Hara Yuko Ito Makoto Shibutani Toshinori Yoshida

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.7, pp.289-300, 2022 (Released:2022-07-01)

参考文献数

43

被引用文献数

1

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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.

著者

Yukiko Yamazaki-Hashimoto Yuji Nakamura Hiroshi Ohara Xin Cao Ken Kitahara Hiroko Izumi-Nakaseko Kentaro Ando Hiroshi Yamazaki Takanori Ikeda Junichi Yamazaki Atsushi Sugiyama

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.40, no.1, pp.33-42, 2015-02-01 (Released:2014-12-18)

参考文献数

39

被引用文献数

9 11

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Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

著者

Koya Sato Seigo Sanoh Yuji Ishida Chise Tateno Shigeru Ohta Yaichiro Kotake

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.7, pp.277-288, 2022 (Released:2022-07-01)

参考文献数

40

被引用文献数

3

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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.

著者

Yukiko Kimura Fusae T. Nishimura Shuntaro Abe Tatsushige Fukunaga Hideji Tanii Kiyofumi Saijoh

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.34, no.1, pp.89-97, 2009-02-01 (Released:2009-02-01)

参考文献数

32

被引用文献数

10 12

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Class II alcohol dehydrogenase (π-ADH), encoded by alcohol dehydrogenase (ADH4), is considered to contribute to ethanol (EtOH) oxidation in the liver at high concentration. Four single nucleotide polymorphisms (SNPs) were found in the promoter region of this gene. Analysis of genotype distribution in 102 unrelated Japanese subjects revealed that four loci were in strong linkage disequilibrium and could be classified into three haplotypes. The effects of these polymorphisms on transcriptional activity were investigated in HepG2 cells. Transcriptional activity was significantly higher in cells with the -136A allele than in those with the -136C allele. To investigate whether this difference in transcriptional activity caused a difference in EtOH elimination, previous data on blood EtOH changes after 0.4 g/kg body weight alcohol ingestion were analyzed. When analyzed based on aldehyde dehydrogenase-2 gene (ALDH2) 487Glu/Lys genotype, the significantly lower level of EtOH at peak in subjects with -136C/A and -136A/A genotype compared with subjects with -136C/C genotype indicated that -136 bp was a suggestive locus for differences in EtOH oxidation. This effect was observed only in subjects with ALDH2 487Glu/Glu. These results suggested that the SNP at -136bp in the ADH4 promoter had an effect on transcriptional regulation, and that the higher activity of the -136A allele compared with the -136C allele caused a lower level of blood EtOH after alcohol ingestion; that is, individuals with the -136A allele may consume more EtOH and might have a higher risk for development of alcohol dependence than those without the -136A allele.

著者

Ryo Kamata Fujio Shiraishi Kazuichi Nakamura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.3, pp.131-136, 2020 (Released:2020-03-06)

参考文献数

12

被引用文献数

1 5

---

Reproductive disorders in birds are the most characteristic effects of DDT contamination of wildlife. Experimental exposure of avian eggs to the estrogenic substance o,p′-DDT causes abnormal development of the reproductive tract (shortening of the left oviduct and aberrant development of the right oviduct) and eggshell thinning in mature birds, but it is still not known how eggshell thinning occurs in the abnormal oviduct. To fill this information gap, we examined the histology of the uterine part of the oviduct in Japanese quail treated in ovo with o,p′-DDT or a synthetic estrogen, diethylstilbestrol (DES), and we performed immunohistochemical staining for the calcium-binding proteins CALB1, SPP1, and TRPV6. Both o,p′-DDT-treated and DES-treated quail had few, and scattered, gland cells in the left uterus, unlike vehicle controls, in which gland cells tightly occupied the lamina propria. The aberrantly developed right uterus retained all the components of the normal left uterus, but in immature form. Immunostaining for CALB1, SPP1, and TRPV6 was greatly reduced by both o,p′-DDT and DES; SPP1 and TRPV6 immunostaining patterns, in particular, differed distinctly from those in the controls. These findings suggest that CALB1, SPP1, and TRPV6 are molecular factors, decreased production of which is responsible for eggshell thinning. Our findings also could contribute to understanding of the eggshell formation mechanism in birds.

著者

Tingzhu Teresa Meng

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.39, no.5, pp.795-802, 2014-10-01 (Released:2014-09-20)

参考文献数

29

被引用文献数

2 9

---

Volatile organic compounds (VOCs) in polyvinyl chloride (PVC) plastic products readily evaporate; as a result, hazardous gases enter the ecosystem, and cause cancer in humans and other animals. Polyethylene vinyl acetate (PEVA) plastic has recently become a popular alternative to PVC since it is chlorine-free. In order to determine whether PEVA is harmful to humans, this research employed the freshwater oligochaete Lumbriculus variegatus as a model to compare their oxygen intakes while they were exposed to the original stock solutions of PEVA, PVC or distilled water at a different length of time for one day, four days or eight days. During the exposure periods, the oxygen intakes in both PEVA and PVC groups were much higher than in the distilled water group, indicating that VOCs in both PEVA and PVC were toxins that stressed L. variegatus. Furthermore, none of the worms fully recovered during the24-hr recovery period. Additionally, the L. variegatus did not clump together tightly after four or eight days’ exposure to either of the two types of plastic solutions, which meant that both PEVA and PVC negatively affected the social behaviors of these blackworms. The LD50 tests also supported the observations above. For the first time, our results have shown that PEVA plastic has adverse effects on living organisms, and therefore it is not a safe alternative to PVC. Further studies should identify specific compounds causing the adverse effects, and determine whether toxic effect occurs in more complex organisms, especially humans.

著者

Toshiro Niwa Mari Morimoto Takako Hirai Tomomi Hata Misato Hayashi Yurie Imagawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.1, pp.143-146, 2016-02-01 (Released:2016-01-13)

参考文献数

21

被引用文献数

7 16

---

The effects of three kinds of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activity of human hepatic cytochrome P450 (P450 or CYP) were investigated. Metabolic activities of P450s expressed in recombinant Escherichia coli at substrate concentrations around the Michaelis constant were compared in the presence or absence of the antibiotics. Amoxicillin, ampicillin, and piperacillin at 0.5 or 1 mM concentrations neither inhibited nor stimulated CYP2C9-mediated tolbutamide methylhydroxylation, CYP2D6-mediated dopamine formation from p-tyramine, or CYP3A4- or CYP3A5-mediated testosterone 6β-hydroxylation. However, amoxicillin and piperacillin inhibited CYP2C8-mediated aminopyrine N-demethylation at 50% inhibitory concentration of 0.83 and 1.14 mM, respectively. These results suggest that piperacillin might inhibit CYP2C8 clinically, although the interactions between these three penicillin-based antibiotics and other drugs that are metabolized by P450s investigated would not be clinically significant.

著者

Yoshinori Okamoto Takao Tobe Koji Ueda Tatsuyuki Takada Nakao Kojima

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.40, no.2, pp.235-242, 2015-04-01 (Released:2015-03-14)

参考文献数

22

被引用文献数

6 11

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Propolis, a natural product derived from plants by honeybees, is a mixture of several hundred chemicals, including flavonoids, coumaric acids, and caffeic acids, some of which show estrogen-like activity. In this study, the estrogenic activity of crude ethanolic extract of Brazilian propolis was determined using several in vitro and in vivo assays. Propolis was found to bind to human estrogen receptors (ERs). Furthermore, propolis induced the expression of estrogen-responsive genes in ER-positive MCF-7 and Ishikawa cells. These in vitro assays suggest that propolis exerts estrogenic activity; therefore, in vivo experiments were conducted using ovariectomized rats. Oral administration of propolis (55 or 550 mg/kg/day for 3 days) significantly increased uterine wet weight and luminal epithelium thickness in comparison with the corresponding values in the corn oil-treated control group. Moreover, propolis induced ductal cell proliferation in the mammary glands. These effects were completely inhibited by full ER antagonist ICI 182,780, confirming that the effects of propolis are mediated by the ER. Our data show that oral intake of propolis induces estrogenic activity in ER-expressing organs in vivo and suggest that Brazilian propolis is a useful dietary source of phytoestrogens and a promising treatment for postmenopausal symptoms.

著者

Yuhji Taquahashi Shuji Tsuruoka Koichi Morita Masaki Tsuji Kousuke Suga Ken-ich Aisaki Satoshi Kitajima

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.9, no.1, pp.17-21, 2022 (Released:2022-01-18)

参考文献数

10

---

Carbon-nanotube yarn (CNT-Y) made from high-purity, highly crystalized, double-walled carbon nanotubes is an advanced material with excellent electrical conductivity and flexibility; hence, it could potentially be used as a novel electrode for biopotential measurements. To our knowledge, the present study is the first in which CNT-Y electrodes were used to conduct electrocardiography (ECG) and electroencephalography (EEG) on experimental animals. All procedures and biopotential measurements were performed under isoflurane anesthesia. The CNT-Y electrodes were attached to the animals by creating a single interrupting suture on the skin. The lead II electrode configuration was used for ECG recording, i.e., the positive, negative, and body-earth electrodes were placed on the left apex of the auricular surface, the interscapular region, and the cervical region, respectively. The bipolar lead was used for EEG recording, with the exploring and reference electrodes on the bregma and base of the right auricular surface, respectively. Using CNT-Y electrodes, we obtained a clear ECG waveform from rats and a guinea pig; the QRS amplitude was ~1.4 mV. In rats, we obtained an EEG waveform with an amplitude of ~150 µV; the peak frequency was 0.8 Hz and the range was ~3 Hz according to power spectral density analysis. In the guinea pig, we obtained an EEG waveform with an amplitude of ~500 µV; the first peak was 0.1 Hz, the second peak was 1 Hz, and the range was ~3 Hz. These results show that CNT-Y could be used in toxicology studies to easily and inexpensively obtain high-resolution biological signals.

著者

Osamu Ohgoda Ian N. Robinson

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.7, no.2, pp.55-76, 2020 (Released:2020-03-03)

参考文献数

33

被引用文献数

1 4

---

In the inhalation field, lipids such as egg phosphatidylcholine (PC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC), are considered to be generally recognized as safe (GRAS), comprising materials that are endogenous to the lungs and locally present in large quantities. Indeed, PC, DSPC and DPPC may be used to form liposomes which are known to promote an increase in drug retention time and reduce the toxicity of drugs after administration. Unfortunately, published literature guidance about the safety evaluation of these lipids as pharmaceutical excipients for use in inhaled products and about application for marketing authorization, is very limited. The purpose of this article is to review the potential toxicity of DSPC for pulmonary administration. Given the use of air and vehicle controls in a range of inhalation toxicology studies as well as negative genotoxicity and also reproductive toxicity results, it is thought that the use of DSPC is shown to be safe for pulmonary administration.

著者

Kohei Matsunaga Jun Abe Keiko Ogata Satoki Fukunaga Sachiko Kitamoto

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.12, pp.601-609, 2021 (Released:2021-12-01)

参考文献数

27

被引用文献数

2

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Epyrifenacil, one of the protoporphyrinogen oxidase (PPO)-inhibiting herbicides, is hepatotoxic in rodents. Previous in vitro assays detected species differences in both kinetics (active hepatic uptake) and dynamics (PPO inhibitory activity) of S-3100-CA, which is a causal metabolite of the hepatotoxicity, suggesting that humans are less sensitive to the epyrifenacil-induced hepatotoxicity than are rats and mice. To elucidate the species differences in the epyrifenacil-induced hepatotoxicity between mice and humans simultaneously, this study fed epyrifenacil to chimeric mice with humanized liver with low replacement index of human hepatocytes. The distribution of S-3100-CA in the liver and subsequent protoporphyrin IX (PPIX) accumulation, an index of PPO inhibition, were compared between human and host mouse hepatocytes using mass spectrometry imaging (MSI) analysis of chimeric liver. The results showed that S-3100-CA and PPIX were significantly colocalized in regions of the liver slice containing host mouse hepatocytes, and thus it was suggested that epyrifenacil had significantly less effect on human livers than mouse livers because of the species differences in both kinetics and dynamics of S-3100-CA. Moreover, the hepatic uptake assay using cryopreserved primary hepatocytes of rats, mice and humans with inhibitors revealed that S-3100-CA is a substrate of organic anion transporting polypeptides (OATPs). These data corroborate the contribution of OATPs to hepatocellular uptake of S-3100-CA, especially in mice, and subsequent PPIX accumulation by more potent S-3100-CA-induced PPO inhibition in mice. MSI analysis of chimeric mice with humanized liver is a useful technique for elucidating species differences in pharmacokinetics and subsequent changes in toxicological biomarkers.

著者

Noriyuki Nakatsu Yoshinobu Igarashi Taiki Aoshi Isao Hamaguchi Masumichi Saito Takuo Mizukami Haruka Momose Ken J. Ishii Hiroshi Yamada

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.42, no.4, pp.491-497, 2017-08-01 (Released:2017-07-13)

参考文献数

28

被引用文献数

7 15

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Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.

著者

Michael W. Bolt Joseph T. Brady Lawrence O. Whiteley K. Nasir Khan

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.2, pp.57-68, 2021 (Released:2021-02-02)

参考文献数

57

被引用文献数

1 25

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The number of gene therapies in development continues to increase, as they represent a novel method to treat, and potentially cure, many diseases. Gene therapies can be conducted with an in vivo or ex vivo approach, to cause gene augmentation, gene suppression, or genomic editing. Adeno-associated viruses are commonly used to deliver gene therapies, but their use is associated with several manufacturing, nonclinical and clinical challenges. As these challenges emerge, regulatory agency expectations continue to evolve. Following administration of rAAV-based gene therapies, nonclinical toxicities may occur, which includes immunogenicity, hepatotoxicity, neurotoxicity, and the potential risks for insertional mutagenesis and subsequent tumorgenicity. The mechanism for these findings and translation into the clinical setting are unclear at this time but have influenced the nonclinical studies that regulatory agencies are increasingly requesting to support clinical trials and marketing authorizations. These evolving regulatory expectations and toxicities, as well as future nonclinical considerations, are discussed herein.

著者

Tomonori Miura Yusuke Kamiya Shiori Hina Yui Kobayashi Norie Murayama Makiko Shimizu Hiroshi Yamazaki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.11, pp.695-700, 2020 (Released:2020-11-02)

参考文献数

26

被引用文献数

1 9

---

Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro–in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.

著者

Musubu Takahashi Ruri Iwai Ryoko Takasawa Tsuyoshi Nakano Tomoya Fujie Takato Hara Yasushi Hara Chika Yamamoto Toshiyuki Kaji

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.7, pp.341-344, 2021 (Released:2021-07-01)

参考文献数

11

被引用文献数

3

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Reactive sulfur species (RSS) include biological persulfide molecules that protect cells against oxidative stress and heavy metal toxicity. Vascular endothelial cells regulate blood coagulation and fibrinolytic activity, and prevent vascular disorders such as atherosclerosis. We hypothesized that RSS protect vascular endothelial cells not only from nonspecific cell damage but also from specific functional damage through regulation of specific cell functions. In the present study, cultured bovine aortic endothelial cells were treated with sodium trisulfide, a sulfane sulfur donor, and both [3H]thymidine incorporation and effects on cell cycle were analyzed. These results suggest that RSS stimulate vascular endothelial cell proliferation. RSS may reduce the functional cytotoxicity of antiproliferative agents.

著者

Yo Shinoda Yuta Yamada Eiko Yoshida Tsutomu Takahashi Yayoi Tsuneoka Komyo Eto Toshiyuki Kaji Yasuyuki Fujiwara

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.6, pp.303-309, 2021 (Released:2021-06-01)

参考文献数

52

被引用文献数

1

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Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure.

著者

Chie Yokouchi Yukari Nishimura Hirohiko Goto Makoto Sato Yuya Hidoh Kenji Takeuchi Yuji Ishii

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.1, pp.31-42, 2021 (Released:2021-01-05)

参考文献数

49

被引用文献数

5

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Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N1-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM.

著者

Yuichiro Takanami Nobumasa Kitamura Shigeaki Ito

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.12, pp.769-782, 2020 (Released:2020-12-01)

参考文献数

25

被引用文献数

2

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A novel tobacco vapor product (NTV) contains tobacco leaves and generates nicotine-containing aerosols using heating elements. Subchronic biological effects have been evaluated previously using three-dimensional bronchial epithelial model cells by repeated exposure to cigarette smoke (CS) and the NTV aerosols; however, the intracellular exposure characteristics have not been studied in detail. In this study, cells were initially exposed to an aqueous extract (AqE) of cigarette smoke (CS) at two concentration levels, and the cell lysate underwent untargeted analysis by LC-high resolution mass spectrometry to determine the exogenous compounds present in the cells. Among the thousands of peaks detected, four peaks showed a CS-dependency, which were reproducibly detected. Two of the peaks were nicotine and nicotine N-oxide, and the other two putative compounds were myosmine and norharman. The cells were then exposed to an AqE of CS in various combinations of exposure and post-exposure culture durations. Post-exposure culturing of cells with fresh medium markedly decreased the peak areas of the four compounds. The in-vitro switching study of CS to NTV aerosols was investigated by intermittently exposing cells to an AqE of CS four times, followed by exposure to either an AqE of CS, NTV aerosol or medium another four times. Switching to NTV reduced myosmine and norharman levels, which are known CS constituents. The results indicate that extracellular compounds inside cells reflect the exposure state outside cells. Thus, monitoring functional changes to cells in these exposure experiments is feasible.