Reddy J K, Jirtle R L, Watanabe T K, Reddy N K, Michalopoulos G, Qureshi S A
Cancer Res. 1984 Jun;44(6):2582-9.
The development of a transplantation system by which rat hepatocytes can be implanted and remain viable in the dorsal fascia of two-thirds hepatectomized syngeneic hosts provides an opportunity to examine whether such transplanted hepatocytes retain the capacity to recognize and respond to the peroxisome proliferators 2-[4-(2,2- dichlorocyclopropyl )phenoxy]-2- methylpropionic acid (ciprofibrate), a hypolipidemic drug, and di-(2-ethylhexyl)phthalate (DEHP), an industrial plasticizer. Male F344 rats with transplanted rat hepatocytes were fed a control diet or a diet containing either 0.05% ciprofibrate (w/w) or 2% DEHP (v/w). After 4 weeks, the animals were sacrificed, and transplanted hepatocytes revealed a significant increase in the numerical density of peroxisomes in both ciprofibrate- and DEHP-fed rats. The volume density of peroxisomes in transplanted hepatocytes increased 9.2- and 5.3-fold, respectively, in ciprofibrate- and DEHP-fed rats, whereas the volume density of mitochondria remained essentially unchanged. The magnitude of increase in peroxisome volume density in transplanted hepatocytes was comparable to increases in the volume density of these organelles in the liver parenchymal cells of syngeneic hosts. The present study also demonstrates that hepatocytes isolated from cat liver and heterotransplanted into partially hepatectomized athymic nude mice retain their biological integrity and respond to the peroxisome proliferative effect of ciprofibrate. This observation suggests the possibility that hepatocytes obtained from small segments of liver of humans, primates, and other species and heterotransplanted into nude mice might provide a valuable model system for toxicological evaluation of chemicals. These studies suggest that hepatocytes, irrespective of their location in the body, recognize the peroxisome proliferator or its active metabolite(s), which stimulates the expression of peroxisome-specific genes in these cells.
通过该移植系统，可将大鼠肝细胞植入同基因三分之二肝切除宿主的背侧筋膜并保持存活，这为研究此类移植肝细胞是否保留识别和响应过氧化物酶体增殖剂的能力提供了契机。过氧化物酶体增殖剂包括降血脂药物2-[4-(2,2-二氯环丙基)苯氧基]-2-甲基丙酸（环丙贝特）以及工业增塑剂邻苯二甲酸二(2-乙基己基)酯（DEHP）。给移植了大鼠肝细胞的雄性F344大鼠喂食对照饮食或含0.05%（重量/重量）环丙贝特或2%（体积/重量）DEHP的饮食。4周后处死动物，移植肝细胞显示，喂食环丙贝特和DEHP的大鼠中过氧化物酶体的数量密度均显著增加。喂食环丙贝特和DEHP的大鼠中，移植肝细胞中过氧化物酶体的体积密度分别增加了9.2倍和5.3倍，而线粒体的体积密度基本保持不变。移植肝细胞中过氧化物酶体体积密度的增加幅度与同基因宿主肝实质细胞中这些细胞器体积密度的增加幅度相当。本研究还表明，从猫肝脏分离并异种移植到部分肝切除的无胸腺裸鼠中的肝细胞保持了其生物学完整性，并对环丙贝特的过氧化物酶体增殖作用作出反应。这一观察结果提示，从人类、灵长类动物和其他物种的小块肝脏中获取并异种移植到裸鼠中的肝细胞可能为化学品的毒理学评估提供一个有价值的模型系统。这些研究表明，肝细胞无论在体内的位置如何，都能识别过氧化物酶体增殖剂或其活性代谢物，后者会刺激这些细胞中过氧化物酶体特异性基因的表达。
