Orton T C, Lowery C
J Pharmacol Exp Ther. 1981 Oct;219(1):207-12.
The irreversible binding of [14C]practolol metabolites to mammalian liver microsomes was studied in vitro. Binding occurred by covalent linkage to amino acids of microsomal proteins. The binding reaction was dependent on oxygen, NADPH, reaction time, microsomal protein content and substrate concentration and was inhibited by carbon monoxide, glutathione and albumin. Albumin inhibition resulted in the binding of reactive metabolite(s) to this serum protein. Hamster (Syrian) liver microsomes had the highest rate of binding and 3-hydroxypractolol formation and marmoset the lowest. The reduced binding of [acetyl-14C]practolol compared to [phenyl-14C]practolol to hamster liver microsomes, but not rat, indicated that metabolites with and without the acetyl grouping were bound in this species. The binding of [14C]desacetylpractolol to hamster liver microsomes was greater than the binding of practolol. Sodium fluoride caused both an increase and a decrease of practolol binding to microsomes from pooled hamster livers, whereas there was a consistent increases in binding to microsomes from individual hamster livers. The collective data indicate that electrophilic metabolites of practolol, possibly N-hydroxylation of the acetyl-amino grouping are formed by the microsomal cytochrome P-450-dependent drug metabolizing enzyme system. These metabolites can react irreversibly with tissue and serum proteins which could be sufficiently altered to be recognized as antigens.
在体外研究了[14C]醋氨心安代谢物与哺乳动物肝脏微粒体的不可逆结合。结合是通过与微粒体蛋白的氨基酸共价连接而发生的。结合反应依赖于氧气、NADPH、反应时间、微粒体蛋白含量和底物浓度，并受到一氧化碳、谷胱甘肽和白蛋白的抑制。白蛋白抑制导致活性代谢物与这种血清蛋白结合。仓鼠（叙利亚）肝脏微粒体的结合率和3-羟基醋氨心安的形成率最高，狨猴的最低。与[苯-14C]醋氨心安相比，[乙酰-14C]醋氨心安与仓鼠肝脏微粒体而非大鼠肝脏微粒体的结合减少，这表明在该物种中，有或没有乙酰基团的代谢物都能结合。[14C]去乙酰醋氨心安与仓鼠肝脏微粒体的结合大于醋氨心安的结合。氟化钠导致醋氨心安与仓鼠混合肝脏微粒体的结合增加和减少，而与单个仓鼠肝脏微粒体的结合则持续增加。总体数据表明，醋氨心安的亲电代谢物，可能是乙酰氨基基团的N-羟基化，是由微粒体细胞色素P-450依赖的药物代谢酶系统形成的。这些代谢物可以与组织和血清蛋白发生不可逆反应，这些蛋白可能会被充分改变而被识别为抗原。
