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Hepatic and intestinal changes in rats treated with T-0126, a microsomal triglyceride transfer protein (mtp)
Miyazaki1, Satoko Miwa, Hirohiko Kodama
1Exploratory Toxicology & DMPK Research Laboratories, Tanabe Seiyaku Co., Ltd., Kawagishi, Toda, Saitama, Japan. toshiko@tanabe.co.jp
Abstract:
In the present study, we investigated the potential toxic effects of 2-week oral treatment with T-0126, a novel microsomal triglyceride transfer protein (MTP) inhibitor, on the liver and intestine in male and female rats. Administration of T-0126 decreased serum lipids and resulted in fat accumulation in the liver and the small intestine. In addition, slight changes in the liver, including an increase in serum aminotransferase (AST and ALT) activity, presence of focal inflammatory lesions, and prolongation of PT and APTT were observed after treatment with T-0126. These changes may be related to a mechanism based on malabsorption of fat, fat-soluble antioxidants, and vitamin K, although we cannot exclude other potential mechanisms such as direct cytotoxicity of T-0126.
Insights
T-0126, a novel MTP inhibitor, caused fat accumulation in the liver and intestine in rats. This MTP inhibitor also led to liver enzyme changes and potential vitamin malabsorption.
Area of Science:
- Pharmacology
- Toxicology
- Gastroenterology
Background:
- Microsomal triglyceride transfer protein (MTP) plays a crucial role in lipoprotein assembly and lipid transport.
- Inhibiting MTP is a therapeutic strategy for dyslipidemia, but potential toxicities require thorough investigation.
Purpose of the Study:
- To evaluate the potential toxic effects of a novel MTP inhibitor, T-0126, on the liver and intestine following a 2-week oral administration in rats.
- To identify specific organ changes and biochemical alterations induced by T-0126 treatment.
Main Methods:
- Male and female rats were administered T-0126 orally for two weeks.
- Serum lipid profiles, liver enzymes (AST, ALT), coagulation parameters (PT, APTT), and tissue histology were assessed.
- Lipid accumulation in liver and intestinal tissues was examined.
Main Results:
- T-0126 treatment significantly decreased serum lipids.
- Significant fat accumulation was observed in the liver and small intestine.
- Slight liver changes included increased AST and ALT, focal inflammatory lesions, and prolonged PT and APTT.
Conclusions:
- T-0126, a novel MTP inhibitor, induces hepatic and intestinal fat accumulation in rats.
- Observed liver changes suggest potential toxicity, possibly linked to malabsorption of fats and fat-soluble vitamins (including vitamin K).
- Further studies are warranted to elucidate the precise mechanisms of T-0126 toxicity, considering both malabsorption and direct cytotoxicity.
