Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin.
Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin.
复制标题
用过氧化物酶体增殖剂那非诺平处理的大鼠肝脏假定的癌前病灶中过氧化物酶体酶、细胞色素 P-452 和 DNA 合成得到增强。
作者：
B. Grasl;W. Huber;W. Just;G. Gibson;R. Schulte‐Hermann
过氧化物酶体增殖物（PP）nafenopin（NAF）通过促进以弱细胞质嗜碱性细胞为特征的假定癌前细胞灶亚型，增强了大鼠肝脏中的肿瘤发展。为了阐明这些弱嗜碱性病灶（WBF）的选择性生长优势，我们研究了NAF对其代谢表型和DNA合成的影响。在WBF，以及在其他病灶亚群和肝细胞癌的发生NAF诱导的酶，即过氧化物酶体β-氧化（酰基辅酶A氧化酶，双功能蛋白和硫解酶），过氧化氢酶和细胞色素P-452进行了研究，通过免疫组织化学方法。在未处理的肝脏中，几乎所有病灶的染色强度与周围组织相同。当应用NAF时，大多数肝病灶显示出比非病灶实质明显的酶诱导发生的染色少得多。然而，WBF的亚群表现出更异质性的酶表达模式，从更少到甚至更多的比在邻近组织。在肝细胞癌中也发现了类似的广泛的过氧化物酶体酶表达。然而，平均而言，肿瘤表现出较少的染色和较低的活性过氧化物酶体β-氧化比周围的实质。WBF的DNA合成率总是高于其他病灶亚型和未改变的肝脏。在大约三分之一的这些病灶中，发现DNA合成伴随着过氧化物酶体β-氧化酶表达的升高而增强。总之，WBF可能具有选择性生长优势，因为它们对NAF对DNA合成和过氧化物酶体酶的诱导作用“过度反应”。
The peroxisome proliferator (PP) nafenopin (NAF) enhanced tumor development in rat liver through promotion of a subtype of putative preneoplastic cell foci, characterized by weak cytoplasmic basophilia. In order to elucidate the selective growth advantage of these weakly basophilic foci (WBF) we investigated the effects of NAF on their metabolic phenotype and DNA synthesis. In WBF, as well as in other foci subpopulations and in hepatocellular carcinomas the occurrence of five NAF-inducible enzymes, i.e. of peroxisomal beta-oxidation (acyl-CoA oxidase, bifunctional protein and thiolase), catalase and cytochrome P-452 was studied by immunohistochemical methods. In untreated livers almost all foci were stained with the same intensity as the surrounding tissue. When NAF was applied, most of the liver foci showed considerably less staining than the non-focal parenchyma in which pronounced enzyme induction had occurred. However, the subpopulation of WBF showed a more heterogeneous pattern of enzyme expression varying from less to even more than in the adjacent tissue. A similarly broad range of expression of peroxisomal enzymes was found in hepatocellular carcinomas. On average, however, the tumors exhibited less staining and lower activity of peroxisomal beta-oxidation than the surrounding parenchyma. WBF always showed higher rates of DNA synthesis than other foci subtypes and unaltered liver. In approximately one-third of these foci DNA synthesis was found to be enhanced concomitantly with elevated expression of peroxisomal beta-oxidation enzymes. In conclusion, WBF may have a selective growth advantage as they 'overrespond' to the inducing effects of NAF on DNA synthesis and peroxisomal enzymes.