Fischer G, Ulrich D, Bock K W
Carcinogenesis. 1985 Apr;6(4):605-9. doi: 10.1093/carcin/6.4.605.
Effects of initiators and promoters of hepatocarcinogenesis on UDP-glucuronyltransferase and arylhydrocarbon hydroxylase were investigated in foci of altered hepatocytes. A single administration of N-nitrosomorpholine (75 mg/kg, 24 h after partial hepatectomy) was used for initiation and chronic administration of phenobarbital (0.1% in tap water) for promotion. Histological evidence indicated that ATPase-negative, gamma-glutamyltranspeptidase-positive, and UDP-glucuronyltransferase-positive foci were highly correlated. Based on this evidence ATPase-negative foci were used as a guide to monitor early lesions and to microdissect lyophilized foci and extra-focal tissue. It was found that treatment with N-nitrosomorpholine led to a permanent increase of UDP-glucuronyltransferase activity in foci tissue (3- to 5-fold, detected 180 and 330 days after initiation). In contrast, arylhydrocarbon hydroxylase activity was decreased by 50%. Administration of phenobarbital further increased UDP-glucuronyltransferase activity in focal tissue (up to 9-fold, compared with control liver). However, this further increase of enzyme activity by phenobarbital was reversible. The results suggest that (i) initiation by chemical carcinogens leads to permanent alterations of drug metabolizing enzymes, consistent with increased toxin-resistance of initiated hepatocytes, and (ii) chronic administration of phenobarbital markedly enhances gene expression of UDP-glucuronyltransferase in initiated hepatocytes.
在肝细胞病变灶中研究了肝癌发生的启动剂和促进剂对UDP-葡萄糖醛酸转移酶和芳烃羟化酶的影响。单次给予N-亚硝基吗啉（75mg/kg，在部分肝切除术后24小时）用于启动，长期给予苯巴比妥（自来水中含0.1%）用于促进。组织学证据表明，ATP酶阴性、γ-谷氨酰转肽酶阳性和UDP-葡萄糖醛酸转移酶阳性灶高度相关。基于此证据，ATP酶阴性灶被用作监测早期病变以及对冻干灶和灶外组织进行显微切割的指标。结果发现，用N-亚硝基吗啉处理导致灶组织中UDP-葡萄糖醛酸转移酶活性永久性增加（3至5倍，在启动后180天和330天检测到）。相反，芳烃羟化酶活性降低了50%。给予苯巴比妥进一步增加了灶组织中UDP-葡萄糖醛酸转移酶的活性（与对照肝脏相比高达9倍）。然而，苯巴比妥对酶活性的这种进一步增加是可逆的。结果表明：（i）化学致癌物启动导致药物代谢酶的永久性改变，这与启动的肝细胞对毒素抗性增加一致；（ii）长期给予苯巴比妥显著增强启动的肝细胞中UDP-葡萄糖醛酸转移酶的基因表达。
