Kolanczyk R C, Rutks I R, Gutmann H R
Research Service, Veterans' Administration Medical Center, Minneapolis, Minnesota 55417.
Chem Res Toxicol. 1991 Mar-Apr;4(2):187-94. doi: 10.1021/tx00020a010.
This investigation examines the catalytic effect of bovine serum albumin on the ortho rearrangement of the possible ultimate carcinogen, N-(sulfooxy)-2-(acetylamino)fluorene, generated from N-hydroxy-2-(acetylamino)fluorene by the sulfotransferase(s) in the cytosol of rat liver. With various preparations of cytosol, 55-75% of the substrate, N-hydroxy-2-(acetylamino)-fluorene, was found to rearrange to the nonmutagenic and noncarcinogenic o-(sulfooxy) esters, 1- and 3-(sulfooxy)-2-(acetylamino)fluorene, in the presence of bovine serum albumin, while less than 1% of the substrate rearranged in its absence. In presence of bovine serum albumin the cytosolic reduction of N-(sulfooxy)-2-(acetylamino)fluorene to 2-(acetylamino)fluorene decreased by 60-90% and its solvolytic degradation to 4-hydroxy-2-(acetylamino)fluorene by 80-90%. The covalent interaction of enzymatically generated N-(sulfooxy)-2-(acetylamino)fluorene with the nucleophilic acceptors, N-acetyl-L-methionine and guanosine, was lowered by greater than 90% by addition of bovine serum albumin. These measurements indicated that the albumin-catalyzed ortho rearrangement controls the rates of concurrent metabolic and degradative reactions of N-(sulfooxy)-2-(acetylamino)fluorene. The results are in agreement with previous findings of a catalytic effect of serum albumin on the ortho rearrangement of synthetic N-(sulfooxy)-2-(acetylamino)fluorene. In contrast to its catalytic effect on the formation of o-(sulfooxy) esters from N-(sulfooxy)-2-(acetylamino)fluorene, bovine serum albumin had no effect on the formation of o-(acetylamino)fluorenols. To assess the substrate specificity of bovine serum albumin, its effect on the rearrangement of N-hydroxy-2-(benzoylamino)fluorene, a carcinogenic analogue of N-hydroxy-2-(acetylamino)fluorene, was analyzed under conditions of cytosolic sulfonation.(ABSTRACT TRUNCATED AT 250 WORDS)
本研究考察了牛血清白蛋白对大鼠肝脏胞质中磺基转移酶由N - 羟基 - 2 -（乙酰氨基）芴生成的潜在最终致癌物N -（磺氧基）- 2 -（乙酰氨基）芴邻位重排的催化作用。在不同的胞质制剂中，发现55 - 75%的底物N - 羟基 - 2 -（乙酰氨基）芴在牛血清白蛋白存在的情况下重排为无致突变性和无致癌性的邻 -（磺氧基）酯，即1 - 和3 -（磺氧基）- 2 -（乙酰氨基）芴，而在其不存在时，底物重排的比例不到1%。在牛血清白蛋白存在的情况下，N -（磺氧基）- 2 -（乙酰氨基）芴向2 -（乙酰氨基）芴的胞质还原减少了60 - 90%，其向4 - 羟基 - 2 -（乙酰氨基）芴的溶剂分解降解减少了80 - 90%。通过添加牛血清白蛋白，酶促生成的N -（磺氧基）- 2 -（乙酰氨基）芴与亲核受体N - 乙酰 - L - 甲硫氨酸和鸟苷的共价相互作用降低了90%以上。这些测量结果表明，白蛋白催化的邻位重排控制了N -（磺氧基）- 2 -（乙酰氨基）芴同时发生的代谢和降解反应的速率。结果与先前关于血清白蛋白对合成的N -（磺氧基）- 2 -（乙酰氨基）芴邻位重排的催化作用的发现一致。与它对由N -（磺氧基）- 2 -（乙酰氨基）芴形成邻 -（磺氧基）酯的催化作用相反，牛血清白蛋白对邻 -（乙酰氨基）芴醇的形成没有影响。为了评估牛血清白蛋白的底物特异性，在胞质磺化条件下分析了其对N - 羟基 - 2 -（苯甲酰氨基）芴（N - 羟基 - 2 -（乙酰氨基）芴的致癌类似物）重排的影响。（摘要截短至250字）
