J Toxicol Sci [JOURNAL]
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200 papers
Evaluation of the stability and cross-reactivity of zopiclone and eszopiclone using immunoassay kits.
Saito T, Namera A, Yamamoto R … +2 more , Morita S, Nakagawa Y
J Toxicol Sci · 2026 · PMID 41765457 · Publisher ↗
Zopiclone (ZOP) and eszopiclone (EZOP) are hypnotics belonging to the cyclopyrrolone class, which are metabolized to zopiclone-N-oxide (ZOPNO) and N-desmethylzopiclone (NDZOP), respectively, and finally to 2-amino-5-chlo...
Zopiclone (ZOP) and eszopiclone (EZOP) are hypnotics belonging to the cyclopyrrolone class, which are metabolized to zopiclone-N-oxide (ZOPNO) and N-desmethylzopiclone (NDZOP), respectively, and finally to 2-amino-5-chloropyridine (2A5C) after long-term storage, freezing, and conservation. This study aimed to examine the stability of ZOP and EZOP using a commercially available immunoassay urine screening kit for ZOP. ZOP and EZOP, as well as their metabolites and 2A5C, were analyzed in urine using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Spiked urine samples were used to confirm cross-reactivity for the immunoassay test and to compare the quantitative results of the clinical urine samples. The results indicate that urine samples stored for an extended period or altered postmortem may lead to false-negative results for ZOP, providing important information for interpreting results in cases involving ZOP.
Possible involvement of tubular interleukin-34 in macrophage recruitment during colistin-induced nephrotoxicity in rats.
Matsushita K, Akane H, Akagi JI … +4 more , Morikawa T, Mizuta Y, Ogawa K, Toyoda T
J Toxicol Sci · 2026 · PMID 41765456 · Publisher ↗
Colistin is a cationic cyclic lipopeptide antibiotic used against multidrug-resistant Gram-negative bacteria; however, its clinical application is limited by nephrotoxicity. Although oxidative stress, mitochondrial dysfu...
Colistin is a cationic cyclic lipopeptide antibiotic used against multidrug-resistant Gram-negative bacteria; however, its clinical application is limited by nephrotoxicity. Although oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress are implicated in the primary cytotoxic mechanisms, the secondary inflammatory pathways remain poorly understood. In this study, we aimed to elucidate the mechanisms underlying colistin-induced nephrotoxicity by analyzing the molecular responses of injured renal tubules isolated by laser microdissection (LMD) in a rat model. Six-week-old male Sprague-Dawley rats were subcutaneously administered colistin (0, 15, or 30 mg/kg/day) for 28 days. Increases in serum creatinine and blood urea nitrogen were associated with tubular vacuolation, single-cell necrosis, and regenerative changes in proximal tubules. Immunohistochemistry revealed increased expression of kidney injury molecule-1 (KIM-1) and presence of cleaved caspase-3 in the injured tubules, indicating epithelial regeneration and apoptosis, respectively. LMD-based microarray analysis identified 486 upregulated and 472 downregulated genes in vacuolated/regenerative tubules compared with normal tubules. Pathway analysis indicated activation of immune-related processes, particularly associated with macrophage activation and trafficking, including interleukin-34 (IL-34). In situ hybridization confirmed Il34 mRNA expression in the cytoplasm of the injured tubules, and accumulation of CD68-positive macrophages around KIM-1-positive tubules. Conversely, no significant change was observed in CD163-positive macrophages following colistin treatment, suggesting proinflammatory M1 macrophage predominance. These findings indicate that tubular IL-34 induction and subsequent macrophage recruitment amplify colistin-induced nephrotoxicity at the secondary level, suggesting that proximal tubules function as both primary targets and effectors of inflammation. Targeting the IL-34-related signaling could thus serve as a potential approach to alleviate colistin-induced renal injury.
An exploratory study of sex differences in thallium-induced nephrotoxicity in rats.
Wen S, Aki T, Tojo A … +1 more , Unuma K
J Toxicol Sci · 2026 · PMID 41765455 · Publisher ↗
Sexual dimorphism is recognized in nephrotoxic acute kidney injury, with females being less susceptible than males. Thallium (Tl), a highly toxic heavy metal, induces severe systemic disorders following exposure, includi...
Sexual dimorphism is recognized in nephrotoxic acute kidney injury, with females being less susceptible than males. Thallium (Tl), a highly toxic heavy metal, induces severe systemic disorders following exposure, including gastrointestinal and neurological disorders and renal failure. However, sex-related differences in Tl-induced nephrotoxicity remain poorly understood. Previous studies have shown that Tl preferentially accumulates in the outer medulla of the kidney of male rats, resulting in mitochondrial dysfunction and medullary thick ascending limb (mTAL) injury, characterized by calcium deposits and impaired renal function. This study investigated the effects of Tl on the kidneys of female rats and the underlying mechanisms. TlSO (30 mg/kg) was administered to rats. Nephrotoxicity was measured 2, 5, and 14 days after Tl-administration using biochemical assays of blood and urine samples, histopathology of the kidney, and transcriptome analysis using microarrays. As in male rats, female Tl-loaded rats developed severe renal dysfunction with calcium deposits in the outer medulla within 5 days after Tl administration. The pathological features were similar to those of male rats; however, the mitochondrial oxidative stress and calcium deposits in the medulla were less extensive in female rats than in male rats. These preliminary findings suggest sex-dependent differences, which might be derived from the differences in sex-hormones, in Tl-induced renal injury and suggest potential involvement of differential oxidative stress handling, mitochondrial responses, and transporter activity. These new insights could assist with the development of therapeutic strategies for treating Tl intoxication in humans.
Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.
Loan A, D'Mello R, Li Y … +4 more , Nurkan T, Minic Z, Wang J, Man Chan H
J Toxicol Sci · 2026 · PMID 41621861 · Publisher ↗
Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in ad...
Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.
Clinical features and outcomes of acute paracetamol poisoning in a resource-limited setting: observations from 96 patients in Vietnam.
Duc ND
J Toxicol Sci · 2026 · PMID 41621860 · Publisher ↗
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Comparative cytotoxicity of novel mercury species α-mercuri-acetaldehyde and α-mercuri-acetic acid versus methylmercury in SH-SY5Y cells.
Yamashiro K, Kono S, Katsuzawa T … +8 more , Arae S, Irie R, Fujimoto Y, Takahashi T, Fujiwara Y, Shinkai Y, Kaji T, Shinoda Y
J Toxicol Sci · 2026 · PMID 41621859 · Publisher ↗
Recently, α-mercuri-acetaldehyde (HgCHCHO) and α-mercuri-acetic acid (HgCHCOOH) have been proposed as potential causative agents of Minamata disease. However, their toxicological profiles remain largely unknown. This stu...
Recently, α-mercuri-acetaldehyde (HgCHCHO) and α-mercuri-acetic acid (HgCHCOOH) have been proposed as potential causative agents of Minamata disease. However, their toxicological profiles remain largely unknown. This study aimed to characterize the cytotoxicity, cellular uptake, and efflux mechanisms of these compounds in SH-SY5Y neuroblastoma cells and to compare these properties with those of methylmercury (MeHg). Cell viability was assessed after 24 hr of exposure to MeHg (1-10 µM), HgCHCHO (10-50 µM), or HgCHCOOH (10-50 µM) using the CCK-8 assay. The roles of L-type amino acid transporter 1 (LAT1) and multidrug resistance-associated proteins (MRPs) were evaluated using the inhibitors JPH203 (1 µM) and MK571 (10 µM), respectively. Intracellular mercury accumulation was quantified after 24 hr of exposure to 3 µM of each compound using thermal decomposition-amalgamation atomic absorption spectrometry. All compounds exhibited dose-dependent cytotoxicity, with a relative toxicity order of MeHg (LC: 6.4 µM) > HgCHCHO (LC: 14.6 µM) > HgCHCOOH (LC: 39.2 µM). LAT1 inhibition had minimal effect on MeHg toxicity but slightly attenuated that of HgCHCHO and HgCHCOOH. Conversely, MRP inhibition markedly enhanced MeHg toxicity, modestly increased that of HgCHCHO, and slightly increased that of HgCHCOOH. Cellular mercury accumulation was consistent with cytotoxicity patterns, showing 10-20-fold lower levels for HgCHCHO and HgCHCOOH than for MeHg. HgCHCHO and HgCHCOOH were approximately 2-5-fold less cytotoxic than MeHg and exhibited substantially lower intracellular mercury levels. Our findings suggest that HgCHCHO and HgCHCOOH are unlikely to have neurotoxic potential comparable to that of MeHg.
Caffeine potentiates the dependence induced by central nervous system depressants contained in over-the-counter medications in mice.
Yonemura-Hirata A, Kaizaki-Mitsumoto A, Numazawa S
J Toxicol Sci · 2026 · PMID 41621858 · Publisher ↗
Over-the-counter (OTC) medicines are available without a prescription and are key to the promotion of self-medication. However, they also pose the risks of misuse, overdose, addiction, and abuse. These risks have recentl...
Over-the-counter (OTC) medicines are available without a prescription and are key to the promotion of self-medication. However, they also pose the risks of misuse, overdose, addiction, and abuse. These risks have recently emerged as global public health concerns. An important aspect of OTC drugs in Japan is that they are often combined with drugs with different effects. Although it has been noted that interactions between depressants and stimulants of the central nervous system (CNS) may promote drug dependence, the details remain unclear due to a lack of basic evidence. Therefore, an assessment was conducted to determine the interaction between CNS depressants, including dextromethorphan, diphenhydramine, and bromovalerylurea, and the CNS stimulant caffeine, by employing a conditioned place preference test in mice. Even at low doses, long-term administration of dextromethorphan and diphenhydramine induced place preference. Long-term administration of high-dose bromovalerylurea also induced this effect. The period required for dextromethorphan, diphenhydramine, bromovalerylurea, and morphine to acquire place preference was shortened by co-administration with caffeine, demonstrating that CNS stimulation enhances the preference of these sedatives in mice. Moreover, the preference for these drugs was suppressed by the dopamine D receptor antagonist SCH23390, and by the dopamine D receptor antagonist sulpiride, suggesting that dopamine is involved in the enhancing effect. These findings underscore the need to reconsider the active ingredients and distribution practices of OTC products, as the prolonged or inappropriate use of OTC medications and polypharmacy increases the risk of dependence.
Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy.
Soga S, Nanri H, Sakai H … +10 more , Ichikawa R, Chigusa Y, Urase Y, Yonamine S, Ogiwara T, Kon R, Ikarashi N, Chiba Y, Hosoe T, Ogawa K
J Toxicol Sci · 2026 · PMID 41621857 · Publisher ↗
Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its m...
Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents-cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide-on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.
Elemental impurities in Yataprasen Thai Polyherbal Formulation: source-dependent variation, and analytical method validation.
Angsusing J, Tanaka YK, Chittasupho C … +1 more , Ogra Y
J Toxicol Sci · 2026 · PMID 41621856 · Publisher ↗
The global consumption of complementary and alternative medicine (CAM) has risen dramatically. However, safety concerns persist owing to contamination with elemental impurities. In this study, we optimized and validated...
The global consumption of complementary and alternative medicine (CAM) has risen dramatically. However, safety concerns persist owing to contamination with elemental impurities. In this study, we optimized and validated an analytical method for quantifying four toxic metals, As, Cd, Pb, and Hg, in Yataprasen (YTPS) extract, a complex Thai traditional polyherbal formulation. Samples were obtained from natural collection sites and commercial sources, and the contributions of 13 individual herbs to total impurities were evaluated. Inductively coupled plasma mass spectrometry (ICP-MS) was applied following four acid-digestion protocols. Quantification involved external calibration and standard addition, with validation covering LOD, LOQ, linearity, precision, and recovery. Toxicological risk was assessed in accordance with the ICH Q3D(R2) guideline. Digestion with 1 mL of HNO gave the highest accuracy and recovery. Cd and Pb levels showed little variation across methods. Validation demonstrated excellent accuracy (93.6-107.5% recovery), strong linearity (R > 0.998), and low detection limits (<1.5 µg/kg). A significant difference in elemental impurity concentration was observed between the two sources, with the naturally collected YTPS exhibiting markedly higher levels of all four metals than the commercial one. While external calibration was sufficient for commercial samples, standard addition was required for naturally sourced samples to overcome matrix effects. Component analysis identified Allium sativum L., Cymbopogon nardus (L.) Rendle, and Melia azedarach L. as the major contributors to the impurity burden. Source-dependent variation in elemental impurity concentration was observed in YTPS extracts, with natural collection posing a greater toxicological concern. The validated analytical workflow provides a robust platform for quality control and regulatory assessment of traditional polyherbal formulations.
Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells.
Yamashita N, Nozuki H, Yamashita T … +4 more , Tsubaki K, Fukushima R, Yamagata R, Hwang GW
J Toxicol Sci · 2026 · PMID 41621855 · Publisher ↗
The causative agent of Minamata disease, which is characterized primarily by severe central nervous system dysfunction, is methylmercury; however, the mechanisms underlying methylmercury toxicity remain unclear. Ferropto...
The causative agent of Minamata disease, which is characterized primarily by severe central nervous system dysfunction, is methylmercury; however, the mechanisms underlying methylmercury toxicity remain unclear. Ferroptosis is a type of programmed cell death that is mediated by iron-dependent lipid peroxidation and methylmercury has long been suggested to cause neuronal damage via lipid peroxidation, although the detailed mechanism of this action remains unknown. In this study we therefore investigated the involvement of ferroptosis in methylmercury-induced neuronal cell death using C17.2 mouse neural stem cells. First, we examined the effects of various ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, and deferoxamine) on methylmercury-induced cell death. All the inhibitors tested attenuated methylmercury-induced cell death. We then examined the levels of intracellular reactive oxygen species and lipid peroxides, and found that these levels were increased prior to methylmercury-induced cell death. We also examined the levels of a cystine transporter (xCT/SLC7A11) and glutathione peroxidase 4 (GPX4), major factors involved in the suppression of ferroptosis. We found that both mRNA and protein levels of xCT were increased prior to methylmercury-induced cell death, whereas GPX4 mRNA levels were largely unaffected by methylmercury and its protein levels were decreased. C17.2 cells overexpressing FLAG-GPX4 exhibited greater resistance to methylmercury than control cells. These results indicate that methylmercury induces ferroptosis in C17.2 cells by suppressing GPX4 protein levels.
Predicting nucleic acid drug-induced nephrotoxicity using a 3D human renal proximal tubule spheroid model.
Morimura K, Takahashi E, Maeda H … +4 more , Nishioka Y, Araki A, Mizumoto H, Jimbo Y
J Toxicol Sci · 2026 · PMID 41500580 · Publisher ↗
Nucleic acid drugs hold considerable promise; however, their toxicological profiles are often difficult to assess in animal models. Clinical studies have reported adverse effects, including thrombocytopenia, complement a...
Nucleic acid drugs hold considerable promise; however, their toxicological profiles are often difficult to assess in animal models. Clinical studies have reported adverse effects, including thrombocytopenia, complement activation, hepatotoxicity, and nephrotoxicity. While human cell-based models for hepatotoxicity are advancing, nephrotoxicity assessment remains limited by the scarcity of physiologically relevant kidney cells. In this study, a three-dimensional spheroid model of human primary renal proximal tubule epithelial cells (3D-RPTEC, Nikkiso) was employed to evaluate the nephrotoxicity of nucleic acid drugs. Proteomic profiling revealed enhanced expression of drug transporters and endocytic machinery in 3D-RPTEC compared with two-dimensional cultures. Lipofection enabled efficient intracellular delivery of nucleic acids. Toxicity was assessed using ATP quantification, biomarker analysis (LDH, KIM-1, NGAL), and high-content analysis (HCA). Significant ATP depletion was observed only after prolonged exposure to SPC5001, a nephrotoxic antisense oligonucleotide. In contrast, biomarker expression and HCA facilitated early detection of compound-specific toxicity and implicated endoplasmic reticulum and mitochondrial stress as underlying mechanisms. These findings establish 3D-RPTEC as a sensitive and physiologically relevant platform for predicting the nephrotoxic potential of nucleic acid drugs.
A preliminary evaluation of the applicability of the in vitro to in vivo extrapolation approach to quantitative risk assessment.
Yoshida K, Umano T, Yamada T … +1 more , Matsumoto M
J Toxicol Sci · 2026 · PMID 41500579 · Publisher ↗
The applicability of the in vitro to in vivo extrapolation (IVIVE) approach for the quantitative risk assessment of chemicals was evaluated using the results of mouse uterotrophic bioassays conducted by the Japanese Mini...
The applicability of the in vitro to in vivo extrapolation (IVIVE) approach for the quantitative risk assessment of chemicals was evaluated using the results of mouse uterotrophic bioassays conducted by the Japanese Ministry of Health, Labour and Welfare. Five chemicals were selected. In the uterotrophic bioassay, three chemicals exhibited positive estrogenic activity, whereas two exhibited negative activity. These chemicals were active in 16 in vitro assays that investigated the key events from estrogen receptor (ER) binding (initiating event) to ER-induced proliferation, enabling us to derive IVIVE conversion factors using a physiologically based kinetic model. The oral equivalent doses (OEDs) that were extrapolated from the activity concentrations at the half-maximal response (AC) and the cutoff point (ACC) were compared with those of other key events to determine the critical key event that plays the most important role in the occurrence of uterotrophic responses. For the three chemicals that exhibited positive estrogenic activity, the OEDs from the in vitro AC values for the determined critical events were within a factor of 2 of the lowest observed effect levels in the uterotrophic bioassay. In addition, the OEDs from the ACC values for the critical key events of the two chemicals that exhibited negative activity were higher than the highest dose tested in the bioassay. Based on these findings, the IVIVE approach was largely valid. However, the critical key events that significantly affect in vivo responses need to be appropriately determined to apply the IVIVE approach for the quantitative risk assessment of chemicals.
Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex.
Obara RD, Kato Y, Asaoka Y … +4 more , Oka H, Murata Y, Izawa T, Kuwamura M
J Toxicol Sci · 2026 · PMID 41500578 · Publisher ↗
Steroidogenesis disruption caused by compounds causes vacuolar lesions in the adrenal cortex. However, research on the reversibility of compound-induced adrenal lesions remains limited. In a 4-week oral repeated-dose tox...
Steroidogenesis disruption caused by compounds causes vacuolar lesions in the adrenal cortex. However, research on the reversibility of compound-induced adrenal lesions remains limited. In a 4-week oral repeated-dose toxicity study with a 4-week recovery period in dogs, administration of S-637880-a compound that off-target inhibits steroid hormone synthesis in vitro-resulted in diffuse microvesicular vacuolation, which was considered to reflect excess lipid accumulation in adrenocortical cells. After the 4-week recovery period, these diffuse vacuolar lesions developed into characteristic multifocal macrovesicular vacuolation in the adrenal cortex, making it difficult to evaluate lesion reversibility. Immunohistochemical evaluation suggested that the histopathological changes observed after the recovery period reflected slow degeneration of lipid-laden adrenocortical cells, culminating in cell death accompanied by macrophage activation and aggregation to process apoptotic or necrotic cells and the liberated lipids. These findings are considered to represent a transitional phase in the recovery process. The reversibility of S-637880-induced vacuolar lesions was confirmed in a subsequent 13-week oral repeated-dose toxicity study with a 13-week recovery period. This case study may be helpful in evaluating the reversibility of vacuolar lesions in the adrenal cortex during nonclinical safety assessments and in determining an appropriate recovery periods for assessing adrenal toxicity.
Perillyl alcohol-induced hematological modulations: insights into human blood cells damage, eryptosis, and systemic perturbations.
Basudan AM, Alsughayyir J, Al-Sheikh YA … +1 more , Alfhili MA
J Toxicol Sci · 2026 · PMID 41500577 · Publisher ↗
Perillyl alcohol (POH) is a natural monoterpene with established antitumor activity. Although its anticancer efficacy is well-documented, its impact on normal blood cells, particularly red blood cells (RBCs), remains und...
Perillyl alcohol (POH) is a natural monoterpene with established antitumor activity. Although its anticancer efficacy is well-documented, its impact on normal blood cells, particularly red blood cells (RBCs), remains underexplored. Given the importance of RBC integrity in maintaining homeostasis, this study aims to investigate the hematological effects of POH, focusing on hemolysis, eryptosis, and systemic blood parameters. Erythrocytes collected from June-August 2023 were treated with POH (0.5-2.5 mM) for 24 hr at 37°C. Hemolysis was assessed using photometric assays. Eryptosis was detected by flow cytometry using annexin V, Fluo4/AM, and HDCFDA to quantify phosphatidylserine (PS) translocation, intracellular Ca, and oxidative stress, respectively. Complete blood count (CBC) parameters were also analyzed. POH induced dose-dependent hemolysis, elevated intracellular Ca, and significant PS externalization, indicating increased eryptosis. The hemolytic activity of POH was supported by marked increases in LDH, CK, and AST. Notably, polyethylene glycol (PEG) significantly attenuated hemolysis, suggesting a protective effect. In whole blood, POH reduced RBC count, hemoglobin, and hematocrit, while increasing RDW-CV. Reticulocyte profiling showed elevated immature reticulocyte fraction (IRF) and a medium fluorescence ratio (MFR). Moreover, POH induced leukopenia with immature granulocytes and platelet aggregation. POH disrupts RBC integrity, triggering hemolysis and eryptosis independently of oxidative stress. The observed hematological alterations underscore potential systemic toxicity and highlight the need for further preclinical evaluation to guide its therapeutic use in oncology.
Evaluation of toxicokinetic interactions mediated by plasma protein binding during amoxapine intoxication.
Okamoto A, Yamazaki Y, Hattori-Usami N … +3 more , Momo K, Kaizaki-Mitsumoto A, Numazawa S
J Toxicol Sci · 2026 · PMID 41500576 · Publisher ↗
Toxicity enhancement mediated by plasma protein binding during intoxication remains poorly understood. It is known that in mice, brain penetration of amoxapine (AMX) increases nonlinearly with increasing doses; therefore...
Toxicity enhancement mediated by plasma protein binding during intoxication remains poorly understood. It is known that in mice, brain penetration of amoxapine (AMX) increases nonlinearly with increasing doses; therefore, this study investigated its potential to enhance toxicity via plasma protein binding. AMX was added to mouse or human plasma and adjusted to therapeutic, toxic, and lethal concentrations. The plasma protein-binding ratio and free AMX concentration were measured using ultrafiltration and equilibrium dialysis. Furthermore, the binding ratios of varying concentrations of chlorpromazine, which is often co-administered with AMX in cases of overdose, was analyzed in the presence of therapeutic AMX concentrations. The binding ratio of AMX exceeded 90%, thereby demonstrating a high binding rate; however, this ratio was lower in human plasma than in mice. A nonlinear increase in free AMX concentration was observed in mouse plasma, particularly at high concentrations. In contrast, free AMX concentration showed a linear increase in human plasma. Neither the therapeutic nor toxic concentration of chlorpromazine produced any visible effects on the plasma protein binding ratio or the free AMX concentration. These results suggest that protein binding of AMX is more readily saturated in mouse plasma than in human plasma. In addition, chlorpromazine inhibits AMX binding to α-acid glycoprotein; however, AMX may alternatively binds to albumin, which results in no apparent change in the total binding ratio. Further insights into the toxicokinetic interactions mediated by plasma protein binding are also needed for various toxic substances other than AMX.
Effect of blood microsampling (50 μL) on toxicological assessment in rats treated with tacrine, a drug known to have adverse effects that increase neutrophils.
Hattori N, Shibui Y, Tanaka Y … +1 more , Saito Y
J Toxicol Sci · 2026 · PMID 41500575 · Publisher ↗
To promote the 3Rs in toxicological assessment, the recommendation for blood microsampling in toxicokinetic evaluation is noted in the ICH Harmonized Guideline S3A Q&As. However, there are only a few articles reporting t...
To promote the 3Rs in toxicological assessment, the recommendation for blood microsampling in toxicokinetic evaluation is noted in the ICH Harmonized Guideline S3A Q&As. However, there are only a few articles reporting the practical application of microsampling in the toxicological assessment with toxic drugs. In this study, we investigate the effect of microsampling on toxicological assessment in rats treated with tacrine, which is known to have toxic effects that induce an increase in neutrophils and behavioral abnormalities. Thirty female Sprague-Dawley rats were divided into microsampling (MS) and non-microsampling (non-MS) groups, and orally administered tacrine once daily at dose levels of 0 (vehicle only), 3 and 10 mg/kg bw for 28 days (each group: n=5). In the MS group, blood samples (50 μL/time point) were collected at 6 time points on day 1 and 7 time points on day 28 to 29. All the animals underwent necropsy on day 29. By comparing the results of toxicological and toxicokinetic analysis between the MS and non-MS groups, we validated effects of microsampling for toxicological assessment. Although increase in neutrophils and repeated stereotypic behaviors were observed as toxic effects in the rats administered tacrine, we could not find any difference between the MS and non-MS groups, and also found that microsampling did not affect any other data from toxicological and toxicokinetic analysis. In conclusion, blood microsampling appeared to be a feasible technique for the toxicity study of tacrine and was considered to be applicable in the toxicity study of even drugs with toxic effects on hematological parameters, such as an increase in neutrophils.
False negatives in the modified ESR-based photosafety test (ESR-PT) caused by ultraviolet-C light.
Hinoshita M, Maeda Y, Kawai A … +1 more , Takeyoshi M
J Toxicol Sci · 2026 · PMID 41500574 · Publisher ↗
The modified electron spin resonance (ESR)-based photosafety test (ESR-PT) is a non-animal prediction test using ESR spectroscopy that is applicable to hydrophobic and colored chemicals and the results show high concorda...
The modified electron spin resonance (ESR)-based photosafety test (ESR-PT) is a non-animal prediction test using ESR spectroscopy that is applicable to hydrophobic and colored chemicals and the results show high concordance with existing photosafety reference information. The modified ESR-PT is based on the detection of singlet oxygen and free radical photoproducts generated from chemicals in the presence of 4-hydroxy-2,2,6,6-tetramethyl-piperidine (4-hydroxy-TEMP). We obtained false-negative results caused by signal increment of the control solution, which is used as the denominator of the classifier in the modified ESR-PT, when we used a different type of lighting unit (type I) to the previously used type of lighting unit (type II). Spectral measurement of the irradiated light from the light sources revealed that the type I lighting unit emitted stronger UV-C light than the type II lighting unit. Consequently, as UV-C absorption of 4-hydroxy-TEMP (λ<210 nm) was confirmed, we repeated the modified ESR-PT using a type I lighting unit equipped with a UV-C cut filter, which led to an apparent decrease of the signal increment in the control solution, and all the false-negative-judged chemicals correctly tested positive but a false positive result was also noted. Therefore, installation of a UV-C cut filter in the lighting unit in modified ESR-PT appears to be a reliable solution for avoiding UV-C light-mediated false-negative results. However, it may also be necessary to reconsider the classifier used in ESR-PT to avoid obtaining false-positive results when using a UV-C cut filter.
Renal effects of excessive fructose intake in Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats.
Toyoda K, Takahashi T, Tanaka Y … +5 more , Suzuki Y, Yokoyama H, Shoda T, Chambers JK, Uchida K
J Toxicol Sci · 2025 · PMID 41320263 · Publisher ↗
Excessive fructose intake has been reported to increase the risks of obesity, diabetes and kidney diseases, including diabetic nephropathy. We investigated the effects of a high-fructose diet on nephropathy in both male...
Excessive fructose intake has been reported to increase the risks of obesity, diabetes and kidney diseases, including diabetic nephropathy. We investigated the effects of a high-fructose diet on nephropathy in both male and female Spontaneously Diabetic Torii-Lepr (SDT fatty) rats, a model for obese type 2 diabetes. 11-week-old male and female Sprague-Dawley (SD) and SDT fatty rats that developed diabetes were each divided into 2 groups receiving either a high-fructose diet (60% fructose) or a basal diet. The diets were fed ad libitum for 7 weeks. Body weights, food consumption, clinical chemistry, urinalysis, kidney weights and histopathology of the kidneys were evaluated. In the SDT fatty rats, fructose intake increased the urinary excretion of calcium and inorganic phosphate in both sexes. Histopathological examination revealed that fructose intake worsened nephropathy (mineralization, inflammatory cell infiltration, and increased mesangial matrix in the glomeruli) in the female SDT fatty rats. In conclusion, a 7-week high-fructose diet induced several renal changes in SDT fatty rats, including urinary electrolyte imbalances and associated mineral deposition in the kidney, suggestive of urinary stone formation. It suggests that the SDT fatty rat is a useful model to investigate type 2 diabetes and diabetic nephropathy and that excessive fructose intake can be a risk factor for the development and progression of urinary stone formation and diabetes- related kidney injury.
Protective effects of retinoic acid on cadmium toxicity in human proximal tubular epithelial cells.
Lee JY, Mori C, Tokumoto M … +1 more , Satoh M
J Toxicol Sci · 2025 · PMID 41320262 · Publisher ↗
Cadmium (Cd) is a toxic heavy metal that induces proximal tubular cell damage. Previously, we identified that retinoic acid receptor (RAR) activity was suppressed in the kidney of Cd-exposed mice. In addition, peroxisome...
Cadmium (Cd) is a toxic heavy metal that induces proximal tubular cell damage. Previously, we identified that retinoic acid receptor (RAR) activity was suppressed in the kidney of Cd-exposed mice. In addition, peroxisome proliferator-activated receptor δ, PPARδ, contributed to the modification of Cd toxicity in HK-2 human proximal tubular cells. In this study, we investigated the protective effects of retinoic acid (RA) and its precursor, retinol, against Cd-induced cytotoxicity in HK-2 cells. Pretreatment with RA or retinol significantly reduced Cd toxicity. Knockdown of RARA, RARG, or PPARD did not alter the protective effects of RA; moreover, the double knockdown of RARA and RARG partly suppressed the RA-reduced Cd toxicity. This suggested that RA may reduce Cd toxicity by a receptor-independent mechanism. Furthermore, RA did not affect the expression of metallothionein genes (MT-1X and MT-2A) or the intracellular accumulation of Cd after Cd treatment. RA pretreatment suppressed Cd-induced apoptosis, partly by inhibiting caspase-3 activation. These findings suggest that RA prevents Cd toxicity via a novel, receptor-independent mechanism involving the suppression of apoptosis.
Quantitative analysis of Cyp1a2 expression and temporal characterization of zonation structure formation during mouse liver development.
Ichikawa M, Yagi M, Miyazawa K … +3 more , Muto H, Kato H, Ochiai W
J Toxicol Sci · 2025 · PMID 41320261 · Publisher ↗
Asthma attacks during pregnancy can cause inadequate oxygen supply to the fetus because the mother cannot get enough oxygen into her bloodstream. Even during pregnancy, medication such as theophylline is needed to avoid...
Asthma attacks during pregnancy can cause inadequate oxygen supply to the fetus because the mother cannot get enough oxygen into her bloodstream. Even during pregnancy, medication such as theophylline is needed to avoid asthma seizure. Theophylline is metabolized by (Cytochrome P450) CYP1A2 in the maternal liver. On the other hand, whether theophylline transferred from the mother to the fetus is metabolized in its liver depends on the degree of CYP1A2 expression, but no such information is available. In the adult liver, CYP1A2 forms zonation structures to efficiently metabolize drugs and foreign substances. In this study, we quantitatively analyzed the expression levels of mCyp1a2 mRNA and protein in the liver throughout development, from fetal and neonatal stages to adulthood, while distinguishing between males and females. In addition, to determine the timing of the mCyp1a2 zonation, analysis was performed in fetal and neonatal livers. We found that mCyp1a2 males and females express very little mCyp1a2 in the fetal liver. One week after birth, mCyp1a2 protein expression was 24% and 14% of adult expression in males and females, respectively. Furthermore, the expression level of mCyp1a2 in both sexes was almost the same as that of adults after 28 days of age. In addition, they found that the zonation of mCyp1a2 begins to form 5 days after birth. It was found that mCyp1a2 expression is very low in the fetal liver, while the liver of a 14-day-old (P14) has approximately half the drug-metabolizing capacity compared to that of an adult liver.
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