Hotchkiss J A, Kim H, Hahn F F, Novak R F, Dahl A R
Inhalation Toxicology Research Institute, Lovelace Biomedical Environmental Research Institute, Albuquerque, NM 87185, USA.
Toxicol Lett. 1995 Jun;78(1):1-7. doi: 10.1016/0378-4274(94)03223-t.
Previous research has shown that i.p. injection of rats with pyridine results in a significant increase in immunoreactive renal cytochrome P4502E1 (alcohol-inducible form) in a dose- and time-dependent manner. However, the cellular location of renal P4502E1 in rats was not reported. Thus, it was not known whether the pyridine-induced increase in renal P4502E1 resulted from increased production of the enzyme in cells which normally express P4502E1 or from de novo expression in cells normally devoid of the protein. To address these questions, rats were injected i.p. with either 200 mg pyridine/kg body wt./day for 1, 2, 3, or 4 days (n = 2/group) or injected once with an equal volume of sterile, pyrogen-free saline (control group; n = 2). Kidney tissue samples from saline- and pyridine-exposed rats were processed by light microscopy and were immunochemically stained to detect rat cytochrome P4502E1. Most of the immunoreactive P4502E1 was located within renal cortical epithelial cells lining proximal and distal tubules of the cortex with lesser--but consistent--amounts present in tubular epithelial cells within the inner and outer medulla. Pyridine exposure resulted in a 2-3-fold increase in P4502E1 immunoreactivity in proximal cortical tubules surrounding glomeruli and cortical blood vessels. The results of this study demonstrate a cell-specific distribution of cytochrome P4502E1 within the rat kidney and indicate that pyridine exposure results in a selective induction of immunoreactive P4502E1 in tubule epithelial cells which constitutively express this enzyme. The results of this study provide a morphologic basis for interpreting cell-specific nephrotoxicity due to xenobiotics that are biotransformed to toxic metabolites by renal P4502E1.
先前的研究表明，经腹腔注射给予大鼠吡啶后，可导致免疫反应性肾细胞色素P4502E1（酒精诱导型）以剂量和时间依赖性方式显著增加。然而，大鼠肾P4502E1的细胞定位尚未见报道。因此，尚不清楚吡啶诱导的肾P4502E1增加是由于正常表达P4502E1的细胞中该酶产量增加，还是由于通常缺乏该蛋白的细胞中从头表达所致。为了解决这些问题，给大鼠经腹腔注射200mg吡啶/千克体重/天，持续1、2、3或4天（每组n = 2），或一次性注射等体积的无菌无热原盐水（对照组；n = 2）。对来自生理盐水和吡啶处理大鼠的肾组织样本进行光学显微镜检查，并进行免疫化学染色以检测大鼠细胞色素P4502E1。大多数免疫反应性P4502E1位于肾皮质近端和远端小管内衬的肾皮质上皮细胞内，在内髓和外髓的小管上皮细胞中含量较少但较为一致。吡啶暴露导致肾小球和皮质血管周围近端皮质小管中P4502E1免疫反应性增加2至3倍。本研究结果表明细胞色素P4502E1在大鼠肾脏内呈细胞特异性分布，并表明吡啶暴露导致在组成性表达该酶的小管上皮细胞中选择性诱导免疫反应性P4502E1。本研究结果为解释由于被肾P4502E1生物转化为有毒代谢物的外源性物质所致的细胞特异性肾毒性提供了形态学基础。
