Lake B G, Evans J G, Gray T J, Körösi S A, North C J
British Industrial Biological Research Association (BIBRA), Carshalton, Surrey, England.
Toxicol Appl Pharmacol. 1989 Jun 1;99(1):148-60. doi: 10.1016/0041-008x(89)90120-8.
Nafenopin was administered orally for 21 days to male Sprague-Dawley rats (0.5-50 mg/kg/day), Syrian hamsters (5-250 mg/kg/day), Dunkin-Hartley guinea pigs (50 and 250 mg/kg/day), and marmosets (Callithrix jacchus, 50 and 250 mg/kg/day). With the rat, and to a lesser extent in the hamster, nafenopin treatment produced dose-related increases in liver size and induction of peroxisomal (palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidizing enzyme activities. In contrast, in the guinea pig and marmoset, there was no effect on liver size and only comparatively small changes were observed in these enzyme activities. Ultrastructural examination of liver sections from nafenopin-treated rats and hamsters revealed increased numbers of peroxisomes many of which lacked the characteristic crystalline nucleoid. While nafenopin had little effect on peroxisome numbers in either the guinea pig or marmoset, increases in microsomal cytochrome P450 content and mixed function oxidase activities were observed in these species. These results demonstrate marked species differences in nafenopin-induced hepatic peroxisome proliferation with the Syrian hamster being less responsive than the rat and the guinea pig and marmoset being only weakly responsive. As nafenopin is a known hepatocarcinogen in the rat, comparative long-term studies in poorly responsive species, such as the guinea pig and marmoset, may help clarify the role of organelle proliferation in the hepatocarcinogenicity of certain peroxisome proliferators.
将萘非诺平口服给予雄性斯普拉格 - 道利大鼠（0.5 - 50毫克/千克/天）、叙利亚仓鼠（5 - 250毫克/千克/天）、邓金 - 哈特利豚鼠（50和250毫克/千克/天）以及狨猴（绢毛猴，50和250毫克/千克/天），持续21天。在大鼠中，以及在较小程度上在仓鼠中，萘非诺平治疗导致肝脏大小呈剂量相关增加，并诱导过氧化物酶体（棕榈酰辅酶A氧化）和微粒体（月桂酸12 - 羟化酶）脂肪酸氧化酶活性增加。相比之下，在豚鼠和狨猴中，对肝脏大小没有影响，并且在这些酶活性方面仅观察到相对较小的变化。对用萘非诺平处理的大鼠和仓鼠的肝脏切片进行超微结构检查发现，过氧化物酶体数量增加，其中许多缺乏特征性的结晶状核仁。虽然萘非诺平对豚鼠或狨猴的过氧化物酶体数量影响很小，但在这些物种中观察到微粒体细胞色素P450含量和混合功能氧化酶活性增加。这些结果表明，萘非诺平诱导的肝脏过氧化物酶体增殖存在明显的物种差异，叙利亚仓鼠的反应性低于大鼠，而豚鼠和狨猴的反应性较弱。由于萘非诺平在大鼠中是一种已知的肝癌致癌物，在反应性较差的物种（如豚鼠和狨猴）中进行比较长期研究，可能有助于阐明细胞器增殖在某些过氧化物酶体增殖剂致癌性中的作用。
