To investigate the pharmacokinetic characteristics in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of type 2 diabetes and obesity, the expressions of major hepatic CYP enzymes in TSOD and TSNO (Tsumura, Suzuki, non-obesity; control) mice were compared. The 7-month-old TSOD mice, which represented severe obesity/diabetes-related pathophysiology, showed higher expressions of Cyp2c and Cyp3a compared with TSNO mice, while those of Cyp1a and Cyp2e were lower. Cyp3a metabolic activity was also higher in TSOD mice. In the 7-month-old liver, pregnane X receptor (PXR) (nuclear receptor) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) (cofactor) mRNA expression were higher in TSOD mice, possibly playing a role in the altered expression of Cyp3a. This specifically altered CYP expression in TSOD mice suggests that the biotransformation of drugs metabolized by these CYP enzymes differs from that in normal animals. Based on these findings, further investigation on the relationship between altered CYP expression and pathophysiology may be useful in elucidating changes in pharmacokinetics in obese/diabetic patients.
Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.
Thallium (Tl) is one of the most toxic metals known to man, causing acute and often lethal poisoning as a result of accidental, criminal, suicidal, or therapeutic administration. Ingested Tl is rapidly absorbed and widely distributed throughout the body, causing extensive tissue damage. Clinical symptomatology of Tl toxicity is usually nonspecific due to multi-organ involvement (Saddique and Peterson 1983;Chandler and Scott 1986) and the mechanisms of Tl toxicity are not fully defined. Since Tl behaves much like potassium in the body and binds to sulfhydryl groups, it causes: (1) interference with vital potassium-dependent processes, (2) substitution for potassium in (Na + -K + ) activated ATPase, and (3) interference with the activity of the sulfhydryl group containing enzymes (Saddique and Peterson 1983;Chandler and Scott 1986;Douglas et al. 1990). The (Na + -K + )-ATPase enzyme is activated by the substitution of Tl for potassium in rabbit erythrocytes (Gehring and Hammond 1967) and rabbit kidney (Britten and Blank 1968) in vitro, but is competitively inhibited by high levels of Tl (Douglas et al. 1990). If enzyme systems involved in the production or utilization of ATP in vivo are influenced by administration of high doses of Tl, it is thought that changes in ATP concentration in organs such as the kidney and the liver may respond in a dose-dependent manner to increasing concentrations of Tl. In the present study we investigated the relationships between ATP concentration, (Na + -K + )-ATPase activity, and Tl concentration in tissues of mice treated with Tl. MATERIALS AND METHODSFifty male adult ICR mice (Nippon SLC Inc., Shizuoka, Japan) weighing 30-35 g were housed in our university animal center (22°C; 55% humidity, 12-hr light-dark schedule) and had free access to a commercial diet (CE-2; CLEA Japan Inc., Tokyo) and tap water during the experimental period. A solution of thallium sulfate (purity 99.9%, Mitsuwa Chemical Co., Ltd., Tokyo) was prepared in saline and administered intraperitoneally to each of 36 mice at a single dose of 25 mg/kg body weight. Six animals were killed under ethylether anesthesia at 3, 6, 12, 24, 72 hr and 10 d after Tl administration. For control, 8 mice were treated with saline and 1 or 2 animals were killed at each time point. Liver and kidneys were removed from all mice and were quick-frozen using a clamp cooled in liquid Correspondence to: M. Yoshida
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.