Newton J F, Yoshimoto M, Bernstein J, Rush G F, Hook J B
Toxicol Appl Pharmacol. 1983 Jun 30;69(2):307-18. doi: 10.1016/0041-008x(83)90312-5.
Acetaminophen (APAP) produces renal necrosis restricted to the straight segment of the proximal tubule in Fischer 344 (F344) rats. On the other hand, Sprague-Dawley (SD) rats are extremely resistant to the nephrotoxic effects of APAP. Such strain differences may be due to different susceptibilities to the nephrotoxic metabolite, p-aminophenol (PAP). PAP administration in both strains of rats resulted in a renal lesion indistinguishable from the APAP-induced renal lesion in F344 rats. The PAP-induced renal lesions in F344 rats, however, were generally more severe than those in SD rats. PAP-induced renal functional changes (elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) correlated with strain-dependent histopathological changes. Analysis of urinary metabolites over a 24-hr period following PAP administration (200 and 400 mg/kg) indicated that more PAP was excreted as APAP in SD than in F344 rats. Covalent binding of PAP to renal microsomes in vitro was much greater in F344 rats than in SD rats at substrate concentrations less than 5 mM. These results suggest that strain differences in PAP-induced nephrotoxicity may be related to differences in the intrarenal activation of PAP. Furthermore, strain differences in APAP-induced nephrotoxicity may be related to strain differences in the activation of the nephrotoxic metabolite, PAP.
对乙酰氨基酚（APAP）会导致Fischer 344（F344）大鼠的近端肾小管直段出现肾坏死。另一方面，Sprague-Dawley（SD）大鼠对APAP的肾毒性作用具有极强的抵抗力。这种品系差异可能是由于对肾毒性代谢产物对氨基苯酚（PAP）的易感性不同所致。给两种品系的大鼠注射PAP后，所导致的肾损伤与F344大鼠中APAP诱导的肾损伤无法区分。然而，PAP诱导的F344大鼠肾损伤通常比SD大鼠的更严重。PAP诱导的肾功能变化（血尿素氮升高以及肾皮质切片对对氨基马尿酸盐积累的减少）与品系依赖性组织病理学变化相关。在注射PAP（200和400 mg/kg）后的24小时内对尿液代谢产物进行分析表明，与F344大鼠相比，SD大鼠中更多的PAP以APAP的形式排泄。在底物浓度低于5 mM时，体外PAP与F344大鼠肾微粒体的共价结合比SD大鼠中的要大得多。这些结果表明，PAP诱导的肾毒性中的品系差异可能与PAP在肾内的激活差异有关。此外，APAP诱导的肾毒性中的品系差异可能与肾毒性代谢产物PAP激活中的品系差异有关。
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