Boberg E W, Liem A, Miller E C, Miller J A
Carcinogenesis. 1987 Apr;8(4):531-9. doi: 10.1093/carcin/8.4.531.
The hepatocarcinogen 1'-hydroxysafrole (HOS) exhibited weak initiating activity and strong promoting activity for the induction of enzyme-altered foci and tumors in rat liver. Thus, administration of a single dose of HOS to rats 18 h after a 70% hepatectomy, followed by administration of phenobarbital (PB) in the diet for 6 months, induced a low, but statistically significant, number of foci of enzyme-altered cells. This treatment did not result in gross liver tumors, even when the PB treatment was continued for 16 months. Large numbers of enzyme-altered foci developed when HOS was administered in the diet at levels of 0.05-0.25% to rats previously administered a single dose of N,N-diethylnitrosamine (DEN) 24 h after a 70% hepatectomy. Similarly, rats given a single dose of DEN 24 h after a partial hepatectomy and then fed 0.10 or 0.25% of HOS in the diet for 10 months developed a high incidence of hepatocellular carcinomas. In the absence of pretreatment with DEN, dietary administration for at least 4 months of 0.10 or 0.25% of HOS induced significant numbers of enzyme-altered foci; these data and liver tumor induction by continuous feeding of HOS, in the absence of pretreatment with DEN, provide additional evidence for an initiating, as well as a promoting, activity of HOS in rat liver. Concurrent administration of the hepatic sulfotransferase inhibitor pentachlorophenol with HOS in each of the above assays almost completely inhibited the initiating and promoting activities of HOS for the formation of enzyme-altered foci and tumors; these data strongly suggest that both the initiating and promoting activities are mediated by the sulfuric acid ester, 1'-sulfooxysafrole. HOS also exhibited initiating activity in adult mouse liver. Thus, dietary administration of 0.25% of HOS for only 1 month, followed by administration of the hepatic tumor promoter 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene resulted in a high incidence and multiplicity of hepatomas by 10 months. In the absence of the promoter, administration of HOS for only 1 month induced no hepatomas; 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene alone induced only a low incidence. In mice not given the promoter, continuous administration of HOS for 3-6 months was required for hepatoma development by 16 months.
肝癌致癌物1'-羟基黄樟素（HOS）在诱导大鼠肝脏酶改变灶和肿瘤方面表现出较弱的启动活性和较强的促进活性。因此，在70%肝切除术后18小时给大鼠单次注射HOS，随后在饮食中给予苯巴比妥（PB）6个月，可诱导出数量较少但具有统计学意义的酶改变细胞灶。这种处理即使在PB处理持续16个月的情况下也未导致肉眼可见的肝肿瘤。当在70%肝切除术后24小时给大鼠单次注射N，N-二乙基亚硝胺（DEN），然后在饮食中给予0.05 - 0.25%的HOS时，会形成大量的酶改变灶。同样，在部分肝切除术后24小时给大鼠单次注射DEN，然后在饮食中喂养0.10%或0.25%的HOS 10个月，肝细胞癌的发生率很高。在没有用DEN进行预处理的情况下，在饮食中给予0.10%或0.25%的HOS至少4个月会诱导出大量的酶改变灶；这些数据以及在没有用DEN进行预处理的情况下通过持续喂养HOS诱导肝肿瘤，为HOS在大鼠肝脏中的启动活性和促进活性提供了额外的证据。在上述每种实验中，将肝磺基转移酶抑制剂五氯苯酚与HOS同时给药几乎完全抑制了HOS形成酶改变灶和肿瘤的启动活性和促进活性；这些数据强烈表明，启动活性和促进活性均由硫酸酯1'-磺基氧基黄樟素介导。HOS在成年小鼠肝脏中也表现出启动活性。因此，在饮食中给予0.25%的HOS仅1个月，随后给予肝肿瘤促进剂1,4-双[2-(3,5-二氯吡啶氧基)]苯，到10个月时肝癌的发生率和多发性都很高。在没有促进剂的情况下，给予HOS仅1个月不会诱导肝癌；单独给予1,4-双[2-(3,5-二氯吡啶氧基)]苯只会诱导出低发生率的肝癌。在未给予促进剂的小鼠中，需要连续给予HOS 3 - 6个月才能在16个月时发生肝癌。
