Kudo T, Shimada T, Toda T, Igeta S, Suzuki W, Ikarashi N, Ochiai W, Ito K, Aburada M, Sugiyama K
Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Tokyo, Japan.
Xenobiotica. 2009 Dec;39(12):889-902. doi: 10.3109/00498250903242592.
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.
为研究2型糖尿病和肥胖模型——津村、铃木、肥胖、糖尿病（TSOD）小鼠的药代动力学特征，比较了TSOD小鼠和津村、铃木、非肥胖（TSNO，对照）小鼠主要肝脏CYP酶的表达。代表严重肥胖/糖尿病相关病理生理的7月龄TSOD小鼠，与TSNO小鼠相比，Cyp2c和Cyp3a的表达较高，而Cyp1a和Cyp2e的表达较低。TSOD小鼠中Cyp3a的代谢活性也较高。在7月龄肝脏中，孕烷X受体（PXR，核受体）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α，辅助因子）的mRNA表达在TSOD小鼠中较高，可能在Cyp3a表达改变中起作用。TSOD小鼠中这种特定的CYP表达改变表明，这些CYP酶代谢的药物的生物转化与正常动物不同。基于这些发现，进一步研究CYP表达改变与病理生理之间的关系，可能有助于阐明肥胖/糖尿病患者药代动力学的变化。
