期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 363, 期 -, 页码 47-56出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2018.11.007
关键词
Antipsychotics; Clozapine; OCTN2; L-camitine; Renal excretion; Liver lipid metabolic disorder
资金
- National Natural Science Foundation of China [81773804]
- Zhejiang Province Natural Science Foundation of China [Z17H300003]
- Fundamental Research Funds for the Central Universities [2016FZA7015]
Clozapine, an atypical antipsychotic drug, is widely utilized for the treatment of schizophrenia; however, dozapine-induced metabolic disorders, such as fatty liver and weight gain, warrant increased attention. Considering the crucial role of L-carnitine (L-Car) in fatty acid oxidation and carnitine/organic cation transporter (OCTN) 2 in renal reabsorption of L-Car, we aimed to study whether clozapine-induced liver lipid metabolic disorder is associated with L-Car dysregulation via inhibition/down-regulation of renal OCTN2. Our results reveal that clozapine inhibits L-Car uptake in MDCK-hOCTN2 cells with an IC50 value of 1.78 mu M. Additionally, clozapine significantly reduces the uptake of L-Car in HK-2 cells, mouse primary cultured proximal tubular (mPCPT) cells and HepG2 cells. Acute (intraperitoneal injection) and 21-day successive oral administration of clozapine at 12.5, 25, and 50 mg/kg to mice resulted in 2-3-fold greater renal excretion of L-Car than in the vehicle group, and the concentration of L-Car in plasma and liver was significantly decreased. Concomitantly, mRNA and protein levels of mOctn2 in the kidney were markedly down regulated. Additionally, 28-day oral administration of clozapine induced increased triglyceride (TG) and total cholesterol (TCHO) levels in mouse livers, while L-Car (40 mg/kg - 1 g/kg) attenuated clozapine-induced liver TG and TCHO increase in a dose dependent manner. These results indicate that clozapine-induced reduction of L-Car reabsorption via inhibition/down-regulation of renal OCTN2 contributes to liver lipid metabolic disorder. L-Car supplementation is probably an effective strategy to attenuate clozapine-induced abnormal lipid metabolism.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据