The Application Of PPARα Transgenic Mice In Toxicological Evaluation And The Safety Evaluation Of Cassia Seed Drugs Containing Anthraquinone Components

Peroxisome proliferators-activated receptors (PPARs) are ligand-activated receptors of nuclear receptor family, there are three different subtypes, including α, α, γ. PPARα controls oxide enzyme, β-oxidation of mitochondria, the uptake of fatty acids and the breakdown of triglycerides through gene transcription, which affects lipid metabolism. In the clinic, PPARa agonist is mainly applied in the treatment of hyper-triglyceridemia. Transgenic animal model is the animal whose genome contains foreign genetic material, we can establish a sensitive strain of animal and the animal model which has same disease with human. In drug safety evaluation, compared with conventional animal models, transgenic animal model has high sensitivity, high reliable, and the external implementation is strong. In this study, we use PPARa transgenic mice to evaluate the toxicity of clofibrate and indomethacin to research whether the PPARa transgenic mice is a more sensitive animal mode in the evaluation of toxicity of PPARa agonist.1. Clofibrate toxicity test28 PPARa transgenic mice and C57BL/6J mice with half males and half females, were randomly divided into high dose group (400 mg/kg of clofibrate), low dose group (300mg/kg of clofibrate) and solvent control group (1% sodium carboxymethyl cellulose). The time of gavage administration lasted 28 days. The haematological index; blood biochemistry; organ coefficient and pathological changes of heart, liver, kidney were tested after the drug administration. The growth of the mice was also observed. Compared with C57BL/6J mice, the PPARa transgenic mouse has the sensibility in evaluation of hepatotoxicity and nephrotoxicity of fibrates PPARa agonist. It is a new animal model.2. Indometacin toxicity test28 PPARa transgenic mice and C57BL/6J mice with half males and half females, were randomly divided into high dose group (3 mg/kg of clofibrate),low dose group (2mg/kg of clofibrate) and solvent control group (1% sodium carboxymethyl cellulose). The time of gavage administration lasted 28 days. The haematological index; blood biochemistry; organ coefficient and pathological changes of liver, kidney were tested after the drug administration. The growth of the mice was also observed. Compared with C57BL/6J mice, the PPARa transgenic mouse has the sensibility in evaluation of hematologic toxicity of indometacin. It is a new animal model.Semen cassiae is the dry and mature seeds of cassia tora or cassia tora L. It has effects such as clearing heat, improving eyesight and looseing the bowel to relieve constipation. In the clinic, it has been used to treat hyperlipidemia, hypertension, constipation. Semen cassia mainly contains anthraquinone compounds (such as emodin, rhubarb phenol), benzopyrazole ketones, protein and amino acids. Anthraquinones is the main active ingredient of it, anthraquinone not only showed a wide range of pharmacological effects, but also show a variety of side effects. In the clinic, taking Anthraquinones laxatives can lead to melanosis coli. In animal experiments, anthraquinone compounds also showed the liver toxicity, renal toxicity, reproductive toxicity. To study the toxicity of semen cassia water extract, we use SD rats to evaluate the toxicity of semen cassiae water extract concentrated solution and semen cassiae water extract freeze-dried powder. In this study, we should observe toxicity target organs, seek maximum non-effect dose and minimum effect dose.1. Acute toxicity study on semen cassiae concentrated solution40 SD rats with half males and half females, were randomly divided into administration group (24g/kg BW), and solvent control group (pure water). The time of gavage administration lasted 1 day. The growth of the mice was also observed after administration. The haematological index; blood biochemistry were tested 7 and 14 days after the drug administration. In our laboratory conditions, there was no dead rat and toxicology change.2. Preliminary test of chronic toxicity of semen cassiae2.1 Subchronic toxicity study on semen cassiae concentrated solution60 SD rats with half males and half females, were randomly divided into high dose group (16g/kg BW), low dose group (8g/kg BW) and solvent control group (pure water). The time of gavage administration lasted 4 weeks. The haematological index; blood biochemistry; organ coefficient and pathological changes of main organs of half of the animals were tested after the drug administration. The rest animal were tested after two weeks. The growth of the mice was also observed. In our laboratory conditions, the maximum non-effect dose is 16g/kg BW.2.2 Subchronic toxicity study on semen cassiae freeze-dried powder40 SD rats with half males and half females, were randomly divided into administration group (20g/kg BW), and solvent control group (pure water). The time of gavage administration lasted 7 weeks. The haematological index; blood biochemistry; organ coefficient and pathological changes of main organs of half of the animals were tested after the drug administration. The rest animal were tested after two weeks. The growth of the mice was also observed. In our laboratory conditions, the minimum effect dose is 20g/kg BW, the toxicity target organs include thymus, spleen, and kidney.