Stalker M J, Towner R A, Kocal T E, Quinn B A, Cameron R G, Hayes M A
Department of Pathology, Ontario Veterinary College, University of Guelph, Canada.
Toxicol Pathol. 1994 Nov-Dec;22(6):579-88. doi: 10.1177/019262339402200602.
Serial magnetic resonance imaging (MRI) was used to evaluate the influences of dietary deoxycholic acid (DCA) on the rate of progression of chemically induced hepatocellular neoplasms in rats. Male Fischer-344 rats with established persistent hepatocellular nodules generated by the Solt-Farber protocol were exposed to dietary DCA (0.3%) between 6 and 12 mo of age. Growth of nodules and carcinomas in vivo was measured by morphometric quantification of tumor images obtained every 6 wk. The final stages of neoplastic progression were determined by terminal histopathological examination and by expression and functional evaluation of glutathione S-transferase (GST) isoenzyme phenotypes. Dietary DCA increased the number of hepatocellular neoplasms per rat, accelerated the rate of growth of persistent nodules, and increased the histological progression of liver tumors. Expression of immunoreactive GST subunits Yf, Ya, and Yb1 was induced in early persistent nodules, a pattern that was maintained throughout the study in both basal diet and DCA-fed groups. However, 5% of early nodules and about 75% of advanced neoplasms were partially or completely deficient in GST Yb2 expression in both groups. DCA did not alter the cytosolic activity for the GST substrates 1-chloro-2,4-dinitrobenzene (CDNB) or trans-4-phenyl-3-buten-2-one (tPBO) in tumors or surrounding liver. However, in both groups, CDNB activity was increased in the tumors relative to the surrounding nonneoplastic tissue, whereas activity for tPBO, a substrate more specific for the Yb2 subunit, was reduced in the tumors. All advanced neoplasms were similarly more resistant than surrounding liver to DNA-binding metabolites of aflatoxin B1 or benzo[a]pyrene. These data demonstrate that DCA can increase the progression of established hepatocellular nodules to larger, more advanced neoplasms but does not preferentially select for a specific GST phenotype. Preferential loss of constitutively expressed GST Yb2 in both basal diet and DCA-fed groups may be an important aspect of progression from resistant nodules to advanced cancers in this model. These studies also demonstrate that serial MRI is a useful tool for measuring the rates of enlargement and patterns of growth in established hepatocellular neoplasms.
采用连续磁共振成像（MRI）评估膳食脱氧胆酸（DCA）对化学诱导的大鼠肝细胞肿瘤进展速率的影响。通过Solt-Farber方案产生持续性肝细胞结节的雄性Fischer-344大鼠在6至12月龄时接受含0.3%DCA的饮食。通过每6周获取的肿瘤图像的形态计量学定量来测量体内结节和癌的生长。通过终末组织病理学检查以及谷胱甘肽S-转移酶（GST）同工酶表型的表达和功能评估来确定肿瘤进展的最终阶段。膳食DCA增加了每只大鼠肝细胞肿瘤的数量，加速了持续性结节的生长速率，并增加了肝肿瘤的组织学进展。免疫反应性GST亚基Yf、Ya和Yb1的表达在早期持续性结节中被诱导，在整个研究过程中，基础饮食组和DCA喂养组均保持这种模式。然而，两组中5%的早期结节和约75%的晚期肿瘤GST Yb2表达部分或完全缺失。DCA未改变肿瘤或周围肝脏中GST底物1-氯-2,4-二硝基苯（CDNB）或反式-4-苯基-3-丁烯-2-酮（tPBO）的胞质活性。然而，在两组中，相对于周围非肿瘤组织，肿瘤中的CDNB活性增加，而tPBO（一种对Yb2亚基更具特异性的底物）的活性在肿瘤中降低。所有晚期肿瘤与周围肝脏相比，对黄曲霉毒素B1或苯并[a]芘的DNA结合代谢产物同样具有更强的抗性。这些数据表明，DCA可增加已形成的肝细胞结节向更大、更晚期肿瘤的进展，但不会优先选择特定的GST表型。基础饮食组和DCA喂养组中组成型表达的GST Yb2的优先缺失可能是该模型中从抗性结节进展为晚期癌症的一个重要方面。这些研究还表明，连续MRI是测量已形成的肝细胞肿瘤的增大速率和生长模式的有用工具。
