Acetaminophen nephrotoxicity in the rat. Renal metabolic activation in vitro.
Acetaminophen nephrotoxicity in the rat. Renal metabolic activation in vitro.
复制标题
对乙酰氨基酚对大鼠的肾毒性。
DOI：
10.1016/0041-008x(83)90161-8
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发表时间：
1983
影响因子：
3.8
通讯作者：
Hook,JB
中科院分区：
文献类型：
--
作者：
Newton,JF;Bailie,MB;Hook,JB
高剂量的对乙酰氨基酚（APAP）导致人和F344大鼠的肝小叶中心和肾皮质坏死。肝坏死被认为是由于通过微粒体细胞色素P-450依赖性系统产生芳基化中间体所致。肾微粒体也通过P-450依赖性机制将APAP代谢为芳基化中间体。因此，至少部分APAP的肾损伤可能是由于类似于肝脏的生化机制。此外，APAP在肾和肝细胞溶质和微粒体中脱乙酰化为对氨基苯酚（PAP）。先前的研究结果表明，PAP可能是通过NADPH非依赖性机制在肾微粒体中激活的。因此，肾脏中APAP的显著代谢活化可能发生在脱乙酰化之后。[ring-14 C]APAP与肾脏亚细胞组分的共价结合用于证实这一假设。在适当的孵育条件下，[ring-14 C]APAP的酶促NADPH非依赖性共价结合可在肾微粒体中得到证实，但在100，000 g上清液组分中未得到证实。这些亚细胞组分的组合导致更大的共价结合[环-14 C]APAP比单独的亚细胞组分。添加谷胱甘肽，双（对硝基苯基）磷酸（脱乙酰酶抑制剂），或PAP抑制这种共价结合。相反，NADPH独立的共价结合[环-14 C]APAP不能证明在任何组合的肝亚细胞组分。比较[环-14 C]APAP和[乙酰基-14 C]APAP与肾10，000 g上清液级分共价结合的实验表明，与肾大分子结合的化合物来源于PAP。因此，这些结果与APAP在脱乙酰化为PAP后可在肾脏中代谢活化的假设一致。
High doses of acetaminophen (APAP) result in hepatic centrilobular and renal cortical necrosis in man and the F344 rat. Hepatic necrosis is considered to be due to the generation of an arylating intermediate via a microsomal cytochrome P-450 dependent system. Renal microsomes also metabolize APAP to an arylating intermediate via a P-450 dependent mechanism. Thus, at least part of the renal damage from APAP may be due to a biochemical mechanism similar to that in liver. Additionally, APAP is deacetylated to p-aminophenol (PAP) in renal and hepatic cytosol and microsomes. Previous results demonstrated that PAP may be activated in renal microsomes via an NADPH-independent mechanism. Therefore, significant metabolic activation of APAP in the kidney may occur subsequent to deacetylation. Covalent binding of [ring-14C]APAP to renal subcellular fractions was used to substantiate this hypothesis. Under appropriate incubation conditions, enzymatic NADPH-independent covalent binding of [ring-14C]APAP could be demonstrated in renal microsomes but not in 100,000g supernatant fractions. Combination of these subcellular fractions resulted in greater covalent binding of [ring-14C]APAP than in the individual subcellular fractions alone. Addition of glutathione, bis(p-nitrophenyl)phosphate (a deacetylase inhibitor), or PAP inhibited this covalent binding. In contrast, NADPH-independent covalent binding of [ring-14C]APAP could not be demonstrated in any combination of hepatic subcellular fractions. Experiments comparing [ring-14C]APAP and [acetyl-14C]APAP covalent binding to renal 10,000g supernatant fractions indicate that the compound which binds to renal macromolecules is derived from PAP. Thus, these results are consistent with the hypothesis that APAP can be metabolically activated in the kidney after deacetylation to PAP.