On the sulfate ester of N-hydroxy-N-2-fluorenylacetamide as a key ultimate hepatocarcinogen in the rat.
On the sulfate ester of N-hydroxy-N-2-fluorenylacetamide as a key ultimate hepatocarcinogen in the rat.
复制标题
N-羟基-N-2-芴基乙酰胺的硫酸酯作为大鼠关键的最终肝癌物质。
作者：
J. Weisburger;R. S. Yamamoto;G. Williams;P. H. Grantham;T. Matsushima;E. Weisburger
通过生物测定、竞争性抑制和生物化学技术研究了N-2-芴基乙酰胺引起大鼠肝脏致癌性所需的生化活化步骤问题。乙酰苯胺不仅能抑制N-2-芴基乙酰胺的肝致癌性，而且能抑制其致癌代谢产物N -羟基化。对于母体化合物，抑制作用主要是由于N -羟基化步骤的竞争，这不适用于N -羟基衍生物。对于后者，在存在抑制性乙酰苯胺的情况下，饮食中添加硫酸钠可恢复N -羟基- N-2-芴基乙酰胺的肝癌性。然而，在N-2-芴基乙酰胺加乙酰苯胺的体系中，硫酸盐的加入不能恢复致癌性，其中抑制作用在于N -羟基化步骤。综合结果证明，硫酸酯形成构成了通过第一活化步骤获得的N -羟基- N-2-芴基乙酰胺对大鼠肝脏致癌性表达所需的第二活化步骤。所需的磺基转移酶系统主要存在于肝细胞质中，但试图将其定位于大鼠肝细胞核组分中，结果仅检测到可疑量。
Summary The problem of the biochemical activation steps required to elicit carcinogenicity to rat liver by N -2-fluorenylacetamide was investigated by bioassay, competitive inhibition, and biochemical techniques. Acetanilide inhibits not only the hepatocarcinogenicity of N -2-fluorenylacetamide but also that of the carcinogenic N -hydroxylated metabolite. With the parent compound, the inhibition was traced chiefly to competition at the N -hydroxylation step, which should not apply to the N -hydroxy derivative. With the latter, the addition of sodium sulfate to the diet restores the hepatocarcinogenicity of N -hydroxy- N -2-fluorenylacetamide in the presence of inhibitory acetanilide. However, sulfate addition fails to return carcinogenicity in the system N -2-fluorenylacetamide plus acetanilide, wherein the inhibition lies at the N -hydroxylation step. The combined results provide evidence that sulfate ester formation constitutes a required second activation step for the expression of carcinogenicity to the liver of rats of N -hydroxy- N -2-fluorenylacetamide, obtained by a first activation step. The required sulfotransferase enzyme system is found mainly in liver cytosol, but attempts to locate it in rat liver nuclear fractions resulted in the detection of only questionable amounts.