THE ROLE OF PARAAMINOPHENOL IN ACETAMINOPHEN-INDUCED NEPHROTOXICITY - EFFECT OF BIS(PARA-NITROPHENYL) PHOSPHATE ON ACETAMINOPHEN AND PARAAMINOPHENOL NEPHROTOXICITY AND METABOLISM IN FISCHER 344 RATS
THE ROLE OF PARAAMINOPHENOL IN ACETAMINOPHEN-INDUCED NEPHROTOXICITY - EFFECT OF BIS(PARA-NITROPHENYL) PHOSPHATE ON ACETAMINOPHEN AND PARAAMINOPHENOL NEPHROTOXICITY AND METABOLISM IN FISCHER 344 RATS
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DOI：
10.1016/0041-008x(85)90413-2
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发表时间：
1985-12-01
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;KUO, CH;HOOK, JB
对乙酰氨基酚（APAP）引起Fischer 344 （F344）大鼠近端小管坏死。最近，对氨基酚（PAP），一种已知的强效肾毒性物质，被鉴定为F344大鼠APAP的代谢物。本研究的目的是确定PAP的形成是否是apap引起肾毒性的必要步骤。因此，我们研究了乙酰氨基酰胺酶抑制剂双（对硝基苯基）磷酸（BNPP）对APAP和PAP肾毒性和代谢的影响。BNPP （1 ~ 8 mm）以浓度依赖的方式降低了F344肾皮质均匀物中APAP去乙酰化和共价结合。在APAP或PAP给药之前用BNPP预处理动物，APAP （900 mg/kg）的肾毒性显著降低，但PAP的肾毒性没有明显降低。这一结果不是由于血浆、肾皮质和肝组织中APAP或乙酰化代谢物的改变。相反，在APAP剂量为750和900 mg/kg后，BNPP预处理使APAP作为PAP排出的比例降低了64%和75%。在PAP剂量为150和300 mg/kg后，BNPP没有改变APAP或其任何非去乙酰化代谢物的排泄，也没有改变PAP或其代谢物的排泄。因此，bnpp诱导的APAP肾毒性的降低似乎是由于抑制APAP去乙酰化。由此可见，体内PAP的形成至少在一定程度上是apap诱导的肾小管坏死的原因。
Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mm) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.