Stout D L, Becker F F
Cancer Res. 1986 Jun;46(6):2693-6.
Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
化学诱导的大鼠肝结节和癌症的特征是激活外源性物质生成反应性物种的能力有限，这主要是由于细胞色素P - 450的量减少。这些病变还通过酶促结合或细胞毒性物质还原等机制显示出外源性物质解毒作用增强。我们最近在自发性小鼠肝肿瘤中也证实了类似的代谢改变模式。这些发现表明，某些归因于慢性化学暴露的表型改变是致癌基因程序所固有的，并且它们可能独立于慢性暴露而出现。为了扩展该研究，我们检测了自发性和二乙基亚硝胺诱导的小鼠肝肿瘤中九种酶的活性，这些酶的活性通常被报道在化学诱导的大鼠肝结节和癌症中发生改变。相对于正常肝脏，自发性肿瘤微粒体中苯并(a)芘单加氧酶（EC 1.14.14.1）、氨基芘脱甲基酶、细胞色素P - 450还原酶、环氧化物水解酶（EC 3.3.2.3）和UDP - 葡萄糖醛酸基转移酶（EC 2.4.1.17）的活性分别为正常肝脏的0.25、0.43、1.27、0.90和0.51。化学诱导肿瘤的微粒体也得到了类似的值。相对于正常肝脏的胞质溶胶，自发性肿瘤胞质溶胶中DT - 黄递酶（EC 1.6.99.2）、谷胱甘肽还原酶（EC 1.6.4.2）、谷胱甘肽S - 转移酶（EC 2.5.1.18）和谷胱甘肽过氧化物酶（EC 1.11.1.9）的活性分别为2.24、2.0、2.43和0.31。化学诱导肿瘤的胞质溶胶也得到了类似的值。这些结果表明，在化学诱导的大鼠肝结节和癌症中观察到的酶表型的很大一部分可能赋予对细胞毒性化学物质的抗性，在自发性和化学诱导的小鼠肝肿瘤中也有体现。此外，表现出这种表型的起始细胞在没有持续化学选择的情况下进行复制和进展。
