Murayama Hirotada, Eguchi Ayumi, Nakamura Misato, Kawashima Masahi, Nagahara Rei, Mizukami Sayaka, Kimura Masayuki, Makino Emi, Takahashi Naofumi, Ohtsuka Ryoichi, Koyanagi Mihoko, Hayashi Shim-Mo, Maronpot Robert R, Shibutani Makoto, Yoshida Toshinori
1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.
2 Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu-shi, Gifu, Japan.
Toxicol Pathol. 2018 Jul;46(5):530-539. doi: 10.1177/0192623318778508. Epub 2018 May 29.
Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.
给予利尿剂螺内酯（SR）可抑制慢性肝病。我们确定了单独使用SR或与抗氧化剂α-糖基异槲皮苷（AGIQ）联合使用对高脂饮食（HFD）喂养的大鼠在两阶段肝癌发生模型中与高脂血症和脂肪变性相关的癌前病变的影响。大鼠喂食对照基础饮食或HFD，并在饮用水中单独给予SR或与抗氧化剂AGIQ联合给予。HFD增加了体重、腹部脂肪组织重量和血浆脂质，而SR和AGIQ共同给药可使其降低。SR和AGIQ共同给药还减少了肝脏脂肪变性和癌前谷胱甘肽S-转移酶胎盘形式阳性灶，同时灶中NADPH氧化酶（NOX）亚基p22phox阳性细胞减少，活性半胱天冬酶-3阳性细胞增加。肝脏基因表达分析显示，SR和AGIQ共同给药改变了生脂酶（Scd1和Fasn）、抗氧化相关酶（过氧化氢酶）、NOX成分（P67phox）和抗炎转录因子（Pparg）的mRNA水平。我们的结果表明，SR与AGIQ联合使用有可能通过降低NOX亚基的表达来抑制与高脂血症和脂肪变性相关的早期肝癌发生。
