Hinson J A
Environ Health Perspect. 1983 Mar;49:71-9. doi: 10.1289/ehp.834971.
Phenacetin can be metabolized to reactive metabolites by a variety of mechanisms. (1) Phenacetin can be N-hydroxylated, and the resulting N-hydroxyphenacetin can be sulfated or glucuronidated. Whereas phenacetin N-O sulfate immediately rearranges to form a reactive metabolite which may covalently bind to protein, phenacetin N-O glucuronide slowly rearranges to form reactive metabolites. Incubation of the purified phenacetin N-O glucuronide under a variety of conditions suggests that N-acetyl-p-benzoquinone imine is a reactive metabolite. This metabolite covalently binds to protein, reacts with glutathione to form an acetaminophen-glutathione conjugate, is reduced by ascorbate to acetaminophen or is partially hydrolyzed to acetamide. (2) Phenacetin can be O-deethylated to acetaminophen, and acetaminophen can be converted directly to a reactive metabolite which may be also N-acetyl-p-benzoquinone imine. (3) Phenacetin can be sequentially N-hydroxylated and O-deethylated to N-hydroxyacetaminophen which spontaneously dehydrates to N-acetyl-p-benzoquinone imine. (4) Phenacetin can be 3, 4-epoxidated to form an alkylating and an arylating metabolite. In the presence of glutathione, a S-ethylglutathione conjugate and an acetaminophen-glutathione conjugate are formed. In the absence of glutathione, the alkylating metabolite may bind to protein and the arylating metabolite is completely hydrolyzed to acetamide and another arylating metabolite which may bind to protein. The structures of the alkylating and arylating metabolites are unknown. Control experiments have shown that in pathway (1) the phenolic oxygen of the acetaminophenglutathione conjugate is derived from water, whereas in pathways (2) and (3) the phenolic oxygen of this metabolite is derived from phenacetin. In pathway (4) the phenolic oxygen was 50% derived from molecular oxygen and 50% from phenacetin. Administration of [p-(18)0]phenacetin to hamsters revealed only a 10% loss of (18)0 in the acetaminophen mercapturic acid (the further metabolic product of the glutathione conjugate) which suggests that, in the hamster, pathways (2) and/or (3) are the primary mechanism of conversion of phenacetin to reactive metabolites in vivo.
非那西丁可通过多种机制代谢为活性代谢产物。（1）非那西丁可被N-羟基化，生成的N-羟基非那西丁可被硫酸化或葡萄糖醛酸化。非那西丁N-O硫酸盐会立即重排形成一种可与蛋白质共价结合的活性代谢产物，而非那西丁N-O葡萄糖醛酸苷则缓慢重排形成活性代谢产物。在各种条件下对纯化的非那西丁N-O葡萄糖醛酸苷进行孵育表明，N-乙酰对苯醌亚胺是一种活性代谢产物。这种代谢产物与蛋白质共价结合，与谷胱甘肽反应形成对乙酰氨基酚-谷胱甘肽共轭物，被抗坏血酸还原为对乙酰氨基酚或部分水解为乙酰胺。（2）非那西丁可O-去乙基化生成对乙酰氨基酚，对乙酰氨基酚可直接转化为一种活性代谢产物，其也可能是N-乙酰对苯醌亚胺。（3）非那西丁可依次进行N-羟基化和O-去乙基化生成N-羟基对乙酰氨基酚，其会自发脱水生成N-乙酰对苯醌亚胺。（4）非那西丁可进行3,4-环氧化形成一种烷基化和一种芳基化代谢产物。在谷胱甘肽存在的情况下，会形成S-乙基谷胱甘肽共轭物和对乙酰氨基酚-谷胱甘肽共轭物。在没有谷胱甘肽的情况下，烷基化代谢产物可能与蛋白质结合，芳基化代谢产物会完全水解为乙酰胺和另一种可能与蛋白质结合的芳基化代谢产物。烷基化和芳基化代谢产物的结构尚不清楚。对照实验表明，在途径（1）中，对乙酰氨基酚-谷胱甘肽共轭物的酚氧来自水，而在途径（2）和（3）中，该代谢产物的酚氧来自非那西丁。在途径（4）中，酚氧50%来自分子氧，50%来自非那西丁。给仓鼠注射[p-(18)O]非那西丁后发现，对乙酰氨基酚巯基尿酸（谷胱甘肽共轭物的进一步代谢产物）中(18)O仅损失10%，这表明在仓鼠体内，途径（2）和/或（3）是非那西丁在体内转化为活性代谢产物的主要机制。
