Fundamental Toxicological Sciences

2020 - Vol. 7

2020 - Vol. 7

Original Article
Comparison of the liver findings after simvastatin-treatment between Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats and Sprague-Dawley rats Vol.7, No.1, p.41-54
Tadakazu Takahashi , Yusuke Suzuki , Naohito Yamada , Kaoru Toyoda , Keisuke Goda , Katsunori Ryoke , Chizuru Matsuura , Akio Kobayashi , Shoichiro Sugai , Kayoko Shimoi
Released: January 28, 2020
Abstract Full Text PDF[3M]

One of the risk factors for drug-induced liver injury (DILI) is the diabetic state. Our previous investigation showed that liver injury after repeated oral dosing with allyl alcohol and carbamazepine was enhanced more in the Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats than in the Sprague-Dawley (SD) rats. It was caused by lower hepatic detoxification due to depleted hepatic glutathione synthesis. This is because simvastatin, frequently used in diabetic patients, shows a positive high reaction in a GSH adduct assay in vitro although the GSH adduction is considered not to be a major metabolic pathway of simvastatin. Therefore, in the present study, effects of simvastatin-treatment on the liver were compared between the Sprague-Dawley (SD) rats and SDT fatty rats in order to obtain additional information to estimate the potential risk of DILI in the diabetic state. There were no effects with simvastatin on the liver in the SD or SDT fatty rats after 13-week oral dosing of simvastatin. These results indicate that simvastatin does not have potential to induce liver injury in diabetic state and are consistent with the reports for the clinical use of simvastatin in the diabetic patients.

Original Article
Triphenyltin inhibits GA-binding protein α nuclear translocation Vol.7, No.1, p.33-40
Naohiro Kidoguchi , Keishi Ishida , Seigo Sanoh , Masatsugu Miyara , Yaichiro Kotake
Released: January 23, 2020
Abstract Full Text PDF[2M]

Organotin compounds such as triphenyltin (TPT), which are common environmental pollutants, had been widely used as antifouling agents for ship bottoms. Although toxic effects of organotins through nuclear receptors such as retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) γ have been well demonstrated, other mechanisms underlying organotin-induced toxicity have hardly been reported. In the present study, we focused on the transcription factor GA-binding protein (GABP), which regulates the expression of various housekeeping genes, as a novel target of TPT toxicity. We investigated the change of GABPα subunit protein expression induced by TPT. Although 100-500 nM concentration of TPT was not found to affect the total protein expression of GABPα, TPT significantly decreased nuclear translocation of GABPα in human embryonic kidney (HEK) 293T cells. In addition, TPT increased intracellular reactive oxygen species (ROS) levels. Both inhibition of GABPα nuclear translocation and the increase in ROS levels were observed in menadione (an ROS inducer)-treated HEK293T cells. Our results indicate that TPT causes inhibition of GABPα nuclear translocation, which may be triggered by ROS production. This might have serious implications in cellular physiology, thereby affecting cell survival.

Original Article
Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels Vol.7, No.1, p.15-31
Misuzu Tanaka , Akane Kanasaki , Noriko Hayashi , Tetsuo Iida , Koji Murao
Released: January 17, 2020
Abstract Full Text PDF[894K]

D-allulose is one of the rare sugars with almost zero calories and several health benefits. Previous studies have reported the safety of D-allulose in normal, overweight/obese, and diabetic humans. However, one study reported significant increases in T-Cho and LDL-C after 12 weeks of D-allulose intake; this report was not a randomized controlled trial and these changes were considered to be due to seasonal variations. We, therefore, conducted a randomized, double-blind, placebo-controlled trial in 90 subjects with high LDL-C levels for 48 weeks to clarify the influence of long-term D-allulose consumption on cholesterol metabolism and efficacy. Subjects were randomly divided into 3 groups: high-dose D-allulose (15 g D-allulose/day), low-dose D-allulose (5 g D-allulose/day), and placebo group (0 g D-allulose/day); each subject consumed a daily test beverage for 48 weeks. Clinical examinations were performed every eight weeks, beginning from initial consumption until week 52. No significant increases in T-Cho and LDL-C between test groups were observed, and 48 weeks of D-allulose consumption did not change risk factors for atherosclerotic cardiovascular disease. Furthermore, no clinical problems were recognized for other parameters. Additionally, significant improvements in hepatic enzyme activities, fatty liver score, and glucose metabolism after long-term D-allulose consumption were observed. The results from our study revealed that 1) D-allulose consumption is considered safe for long-term intake up to a year, and 2) D-allulose may be effective for improving hepatic functions and glucose metabolism.

Letter
Usefulness and limitations of mRNA measurement in HepaRG cells for evaluation of cytochrome P450 induction Vol.7, No.1, p.9-14
Kenta Mizoi , Yuuki Fukai , Eiko Matsumoto , Satoshi Koyama , Seiichi Ishida , Hajime Kojima , Takuo Ogihara
Released: January 15, 2020
Abstract Full Text PDF[1M]

Cytochrome P450s (CYPs) are involved in the metabolism of various drugs, and may generate toxic metabolites or intermediates that result in drug-induced liver injury (DILI). Consequently, inducers of CYPs may promote DILI. In a draft test guideline, the Organisation for Economic Co-operation and Development (OECD) recommends measurement of the metabolic activity of CYP as an index for assessing CYP-inducing activity. However, change of mRNA level has also been used as a simple parameter to evaluate CYP induction. In this study, therefore, we examined the usefulness and limitations of mRNA expression measurement for evaluation of the induction of CYP1A2, CYP2B6, and CYP3A4 by omeprazole, phenobarbital, and rifampicin (RIF), respectively, in HepaRG cells, a well-established cell line derived from human hepatocellular carcinoma. The results of mRNA measurement correlated well with the results of metabolic activity measurement in the lower concentration ranges for all inducers, even though we observed significant decreases in albumin and urea secretion in the presence of 10 µM RIF, reflecting its known hepatotoxicity. Our results indicate that mRNA measurements and metabolic activity measurements in HepaRG cells generally give comparable results for fold-induction of CYPs.

Original Article
Azoxystrobin at sub-cytotoxic concentrations disrupts intracellular zinc homeostasis: A flow cytometric analysis with rat thymic lymphocytes and fluorescent probes Vol.7, No.1, p.1-7
Mai Shoji , Masaki Asada , Akihiko Matsumoto , Haruki Nishino , Ao Yi Xiang , Mizuki Mizobuchi , Naoki Kanematsu , Hajime Miura , Norio Kamemura
Released: January 10, 2020
Abstract Full Text PDF[3M]

Azoxystrobin is a broad-spectrum fungicide having a wide usage. However, the toxic effect of azoxystrobin in humans is not reported. In Japan, azoxystrobin was detected at a five-fold higher concentration than the normal upper limit (2.5 mg/kg) in a shipment of an Australian barley used in different food products. Thus, there is a chance of azoxystrobin exposure through food to humans, and hence it is imperative to study the toxic effects of this compound. In this study, the toxic effect of azoxystrobin was evaluated to predict its adverse effects on human. Azoxystrobin at 3-30 µM (approximately 1.2-12.1 mg/L) raised the intracellular Zn2+ concentration of rat thymic lymphocytes. This increase was due to an influx of extracellular Zn2+ and a release of intracellular Zn2+. Azoxystrobin partially inhibited the temperature-dependent Zn2+ influx, thus jeopardizing the cellular Zn2+ homeostasis. Because Zn2+ is an important intracellular messenger in lymphocytes, this altered Zn2+ homeostasis might lead to adverse effects if the blood concentration of azoxystrobin reaches 3 µM or more in humans. However, by extrapolating the azoxystrobin pharmacokinetics data of rats to human, it can be predicted that such high blood concentration may be unlikely in humans.