科研之友
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摘要
Aims: Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic side-effects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats. Main methods: Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg, equivalent to a human clinical dose of 10 mg) via self-administration aimed to measure pharmacokinetics. Based on the pharmacokinetic analysis, the acute effects of olanzapine on sterol regulatory element binding protein (SREBP)-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR. Key findings: A pharmacokinetic analysis demonstrated that the maximum concentration of olanzapine in plasma (C-max) occurred at 6 h with a peak concentration of 276.5 ng/ml after a single oral treatment and with a plasma elimination half-life of 3.5 h after peak. The mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transport was increased 1.9 8.8 fold compared with the control at 6 h after olanzapine administration but returned to basal level at 12 h post-treatment, while the increased mRNA expression of SREBP-1c and its targeted fatty acid-related genes appeared at both 6 h and 12 h post-treatment. Significance: The present study provided evidence that olanzapine at a clinically-relevant dose caused abnormal expression of genes involved in lipid metabolism in the liver and WAT. These results suggest that olanzapine may cause dyslipidemia side-effects through direct effects on lipid biosynthesis and efflux genes associated with SREBP-stimulated transcriptional changes.
- 出版日期2015-5-1
- 单位重庆大学
