Eacho P I, Foxworthy P S, Johnson W D, van Lier R B
Fundam Appl Toxicol. 1985 Aug;5(4):794-803. doi: 10.1016/0272-0590(85)90204-0.
Compound LY171883 caused dose-related and reversible hepatomegaly in male Fischer 344 rats. Histological examination revealed hepatocellular hypertrophy with no other evidence of liver disease. There were only minor changes in serum glucose, total bilirubin, alkaline phosphatase, and alanine transaminase which were generally unrelated to dose and dissociable from the hepatomegaly. Total liver DNA increased but the DNA concentration decreased, indicating that liver growth involved a combination of hypertrophy and hyperplasia. Total liver protein and RNA increased. Hepatic mitochondrial protein content increased but cytochrome oxidase activity was not changed. There were minor changes in mitochondrial respiratory parameters; however, all the values were in the normal range and there was no indication of mitochondrial toxicity. Microsomal protein, drug-metabolizing activity, and cytochrome P-450 increased, but glucose-6-phosphatase activity was not changed. The induction of drug-metabolizing enzymes and absence of toxicity were evidence that the hepatomegaly was an adaptation to an increased functional load in the liver. An increase in catalase activity suggested that the response may have also involved peroxisomes. In addition to rats, LY171883 administration caused hepatomegaly in mice and hamsters at daily exposures exceeding 100 mg/kg. The response was not observed in guinea pigs, beagle dogs, or rhesus monkeys given maximum tolerated doses, indicating LY171883-induced hepatomegaly is not a response common to all species. The doses required to elicit hepatomegaly greatly exceeded doses that produce pharmacological efficacy in animals and those that are expected to be used clinically. Since humans will not receive doses comparable to those given rodents, and considering that the primate species tested did not experience hepatomegaly, it is unlikely that the effect observed in rodents can be extrapolated to humans.
化合物LY171883在雄性Fischer 344大鼠中引起了剂量相关的可逆性肝肿大。组织学检查显示肝细胞肥大，未发现其他肝病证据。血清葡萄糖、总胆红素、碱性磷酸酶和丙氨酸转氨酶仅有轻微变化，这些变化通常与剂量无关，且与肝肿大无关。肝脏总DNA增加，但DNA浓度降低，表明肝脏生长涉及肥大和增生。肝脏总蛋白和RNA增加。肝线粒体蛋白含量增加，但细胞色素氧化酶活性未改变。线粒体呼吸参数有轻微变化；然而，所有值均在正常范围内，没有线粒体毒性的迹象。微粒体蛋白、药物代谢活性和细胞色素P-450增加，但葡萄糖-6-磷酸酶活性未改变。药物代谢酶的诱导和无毒性表明肝肿大是对肝脏功能负荷增加的一种适应。过氧化氢酶活性增加表明该反应可能也涉及过氧化物酶体。除大鼠外，每日暴露量超过100 mg/kg时，LY171883给药会在小鼠和仓鼠中引起肝肿大。在给予最大耐受剂量的豚鼠、比格犬或恒河猴中未观察到该反应，表明LY171883诱导的肝肿大并非所有物种的共同反应。引起肝肿大所需的剂量大大超过了在动物中产生药理作用的剂量以及预期在临床上使用的剂量。由于人类不会接受与给予啮齿动物相当的剂量，并且考虑到所测试的灵长类动物物种未出现肝肿大，因此不太可能将在啮齿动物中观察到的效应外推至人类。
