Fundamental Toxicological Sciences

2015 - Vol. 2 No. 3

2015 - Vol. 2

Original Article
Effects of dietary fish oil on cytochrome P450 3A expression in the liver of SHR/NDmcr-cp (cp/cp) rats, an animal model for metabolic syndrome Vol.2, No.3, p.127-135
Tohru Yamazaki , Takashi Ohki , Hiroki Taguchi , Asami Yamamoto , Mari Okazaki , Takeshi Sakamoto , Atsushi Mitsumoto , Yoichi Kawashima , Naomi Kudo
Released: August 05, 2015
Abstract Full Text PDF[347K]

Pathophysiological and nutritional conditions often affect the expression of drug-metabolizing enzymes. SHR/NDmcr-cp (cp/cp) rats (SHR/NDcp) are highly suitable as a metabolic syndrome (MS) model. Nevertheless, little is known about the expression profile of cytochrome P450 (CYP) in the liver of SHR/NDcp. We thus attempted to clarify the expression profile of CYP genes and the effect of fish oil (FO) on this profile in the liver of SHR/NDcp. Lower levels of CYP3A2 mRNA and CYP3A activity (testosterone 6β-hydroxylation) were distinctive features in SHR/NDcp compared with their controls (Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), stroke-prone SHR and lean littermates of SHR/NDcp). Differently from CYP3A2, the expression of other CYP isoforms was largely unchanged in SHR/NDcp. The changes in CYP profile observed in SHR/NDcp are similar to those of patients with diabetes and simple hepatic steatosis. Feeding on FO at a high dose (18.8% in the diet) upregulated CYP3A2 gene expression and CYP3A activity in the liver; the extent of these increases was greater in SHR/NDcp than in WKY and lean littermates of SHR/NDcp. This effect was not observed with FO at a normal dose (5% in the diet). These results indicate that, in the context of the CYP profile, SHR/NDcp is an animal model that is suitable for studying MS and imply that FO intake is critical in determining the efficacy or adverse effects of drugs in patients with MS.

Original Article
The concern for uterine carcinogenesis in safety assessments for a new pharmaceutical Vol.2, No.3, p.117-126
Hiroyuki Kuroda , Takashi Yamaguchi , Toshiko Kinomoto , Shuji Ogawa , Atsushi Shiga , Hitoshi Naraoka , Kazuhiko Takamatsu , Yuji Oishi
Released: July 30, 2015
Abstract Full Text PDF[2M]

Acotiamide hydrochloride hydrate (acotiamide-HH) has been newly developed as an indication for functional dyspepsia, which is characterized by digestive symptoms such as postprandial fullness, abdominal bloating, or early satiation, and is now being prescribed in Japan. As part of a safety assessment, 2-year long-term carcinogenicity studies using rats and mice were conducted. In the mouse carcinogenicity study, no evidence of carcinogenicity was obtained, even in the high-dose-treated group (up to 2000 mg/kg/day). In the rat carcinogenicity study, acotiamide-HH was administered at 200, 600, and 2000 mg/kg/day. Detailed histopathological examination revealed that the incidence of endometrial adenocarcinoma significantly increased in the 600 mg/kg/day treated group. There was no trend of this incidence and no accompanying increase in pre-neoplastic lesions or related histological changes in the genital tissues, suggesting the absence of abnormalities in the sexual endocrine system. Results of genotoxicity and reproductive/developmental studies showed that acotiamide-HH is a non-genotoxic substance and did not affect sexual balance. Acotiamide-HH did not induce an estrogen-dominant hormonal imbalance that could cause the incidence of uterine cancer and did not have initiation activity. Therefore, the proliferation of endometrial adenocarcinoma in this middle dose group in the rat carcinogenesis study was considered an accidental event of naturally occurring tumors. However, the incidence of endometrial adenocarcinoma in this group deviated from the background data collected in the same laboratory during the study period. Therefore, it is considered necessary to conduct another pre-clinical study in order to obtain data that would dispel any concerns of safety.

Evaluation of laser irradiance on photodynamic therapy using talaporfin sodium-induced glioblastoma T98G cell death Vol.2, No.3, p.111-116
Yuichi Miki , Jiro Akimoto , Aya Sato , Yasuyuki Fujiwara
Released: June 26, 2015
Abstract Full Text PDF[2M]

In photodynamic therapy (PDT) for glioma patients, apoptosis not necrosis is the desirable mode of cell death, as necrotic cell death induces late appearance of obstacles following PDT. We previously demonstrated that increase in both treatment dose of photosensitizer talaporfin sodium (NPe6) and laser fluence (laser energy density) changes the dominant cell death process from apoptosis to necrosis in glioblastoma T98G cells. Here, we investigated the effect of laser irradiance (laser power density), which is another important parameter of PDT, on PDT-induced cell death modalities in cultured T98G cells. When fluence was fixed at 10 J/cm2, NPe6 dose-dependently reduced the cell viability, regardless of irradiance (11, 22, 33, and 44 mW/cm2). Morphological observations and biochemical analysis (measurement of caspase-3 activity, staining of cell surface-exposed phosphatidylserine, and staining of propidium iodide) further confirmed that increase in dose of NPe6 changed the dominant cell death process from apoptosis to necrosis, regardless of irradiance. We also noted no influence of irradiance level on the leakage of lactate dehydrogenase from T98G cells following PDT treatment. Taken together, our present and previous findings suggest that dose of NPe6 and laser fluence but not laser irradiance are important parameters to consider in PDT using NPe6 in T98G cells.

Positive and negative ions by air purifier have no effects on reproductive function or postnatal growth and development in rats Vol.2, No.3, p.101-110
Dai Yamamoto , Yumi Wako , Shino Kumabe , Kiyoshi Wako , Yukari Sato , Mayumi Fujishiro , Yoshimasa Yasuda , Ikuo Matsuura , Yasuyuki Ohnishi
Released: June 23, 2015
Abstract Full Text PDF[181K]

Air purifiers, which release positive and negative ions generated by electric discharge, are widely used in a variety of places. In this study, male and female SD rats [Crl:CD(SD)] were exposed by whole-body inhalation (6 hr/day) to ionized air containing positive and negative ions for at least 10 weeks before mating and throughout the mating, gestation, and lactation periods over two generations, and the effects on the reproductive function of parental animals and development of offspring were assessed. The concentrations of the ionized air were set at 0 and 7,000,000 ions/cm3 (280- to 1,000-fold higher than normally used in humans) and each group consisted of 24 F0 rats/sex/group and 20 to 23 F1 rats/sex/group. The ionized air had no general toxicological effects on parental animals in the observation for clinical signs, body weight and food consumption measurement, or pathological examination. As for the effects on the reproductive function, there were no exposure-related changes in mating ability, fertility, pregnancy, parturition, or nursing behavior, nor were there any changes in the estrous cycle or sperm parameters in either generation, nor in the ovarian follicle counts (only F1 females). Moreover, there were no effects on litter size, viability, growth, or development of F1 and F2 offspring, including sexual maturation. Therefore, it was suggested that the ionized air has no reproductive or developmental toxicity in rats.

Original Article
Metabolism of trimethylselenonium ion in selenium accumulator, Allium sativum Vol.2, No.3, p.95-99
Yasumitsu Ogra , Yurie Ogihara , Yasumi Anan
Released: June 16, 2015
Abstract Full Text PDF[379K]

To understand selenium (Se) circulation in the biosphere, the metabolism of organic Se, in particular, Se metabolites, in animals and plants should be elucidated. In this study, garlic, Allium sativum, a well-known Se accumulator with high Se metabolic ability, was hydroponically cultivated and then exposed to trimethylselenonium ion (TMSe), a urinary metabolite. Thereafter, the Se concentration in several parts of garlic, such as roots, bulbs, and leaves, was determined. To reveal the metabolic pathway of TMSe, the Se species in A. sativum were investigated by speciation using HPLC hyphenated with an inductively coupled plasma mass spectrometer (LC-ICP-MS). Se was mostly accumulated in the roots. TMSe was detected in the extract of each plant part. However, the amount of Se incorporated from the medium was not completely recovered in the garlic, suggesting that a part of TMSe was metabolized into volatile Se. Consequently, we conclude that the majority of TMSe incorporated into garlic is accumulated as is, the rest is partially desmethylated to form a volatile Se compound, such as a dimethylated Se compound.