Blaauboer B J, van Holsteijn C W, Bleumink R, Mennes W C, van Pelt F N, Yap S H, van Pelt J F, van Iersel A A, Timmerman A, Schmid B P
Research Institute of Toxicology, University of Utrecht, The Netherlands.
Biochem Pharmacol. 1990 Aug 1;40(3):521-8. doi: 10.1016/0006-2952(90)90551-u.
The peroxisome-proliferating effects of clofibric acid and beclobric acid were studied in primary cultures of hepatocytes derived from rat, monkey (Macaca fascicularis) and human liver. Determination of peroxisomal fatty acid beta-oxidation and morphometrical analysis of the peroxisomal compartment were performed after incubation of 1-day-old hepatocyte cultures for 3 days with either compound. In rat liver cell cultures both compounds gave a 10-fold increase in peroxisomal beta-oxidation, a 3-fold increase in the relative number of peroxisomes and a 1.5-fold increase in the mean size of peroxisomes. Beclobric acid gave its maximal effect at a concentration of 10 microM, which is at least one order of magnitude lower than the maximum-effect concentration of clofibric acid. At concentrations greater than 300 microM beclobric acid was cytotoxic. No stimulation of peroxisomal fatty acid beta-oxidation was found in either monkey or human hepatocyte cultures. Morphometrical analysis also showed no increase in the peroxisomal compartment in cultures derived from these species, as indicated by the lack of increase in both relative number and size of peroxisomes. In all three species tested beclobric acid was equally cytotoxic for hepatocytes in vitro. These results are of relevance for the interpretation of the peroxisome-proliferating effects of clofibrate and similar compounds in rats. Since peroxisome proliferation may be correlated to increased hepatic tumour incidences in the rat, the absence of peroxisome proliferation in primates suggests the absence of tumourogenic activity by hypolipidemic compounds in these species.
在源自大鼠、猴（食蟹猴）和人肝脏的原代肝细胞培养物中，研究了氯贝酸和苄氯贝特的过氧化物酶体增殖效应。在用这两种化合物之一对1日龄肝细胞培养物孵育3天后，进行过氧化物酶体脂肪酸β氧化的测定和过氧化物酶体区室的形态计量分析。在大鼠肝细胞培养物中，两种化合物均使过氧化物酶体β氧化增加10倍，过氧化物酶体的相对数量增加3倍，过氧化物酶体的平均大小增加1.5倍。苄氯贝特在浓度为10μM时产生最大效应，该浓度比氯贝酸的最大效应浓度至少低一个数量级。在浓度大于300μM时，苄氯贝特具有细胞毒性。在猴或人肝细胞培养物中均未发现过氧化物酶体脂肪酸β氧化受到刺激。形态计量分析还表明，源自这些物种的培养物中过氧化物酶体区室没有增加，这表现为过氧化物酶体的相对数量和大小均未增加。在所有测试的三个物种中，苄氯贝特对体外肝细胞的细胞毒性相同。这些结果对于解释氯贝特及类似化合物在大鼠中的过氧化物酶体增殖效应具有重要意义。由于过氧化物酶体增殖可能与大鼠肝脏肿瘤发生率增加相关，灵长类动物中不存在过氧化物酶体增殖表明降血脂化合物在这些物种中不存在致瘤活性。
