ラット腎腫瘍発生におけるリン酸塩の促進作用並びにクエン酸カリウムの抑制効果に関する研究

Abstract

Medium organ bioassays to shorten the experimental duration with unilateral nephrectomy for early detection of renal tumors were investigated in male Wistar rats after N-ethyl-N-hydroxyethylnitrosamine (EHEN) administration. Animals were fed 1000 ppm EHEN diet for 2 weeks and the left kidney was removed at week 3. They received several promoting agents and non-promoting agents as negative control for 18 weeks. Within a relatively short period of 20 weeks, the promoting effect on rat renal tumorigenesis can be detected as a significant increase of preneoplastic lesions, such as simple or adenomatous hyperplasias with increased levels of 5-bromo-2'-deoxyuridine (BrdU)-labeled renal cortical tubular epithelia. Various kinds of salts and metals contained in the diet were tested at concentrations more than 20 times the normal doses in a preliminary experiment for nephrotoxicity over 8 weeks. Potassium dibasic phosphate (PDP), potassium aluminum sulfate (PAS) and copper sulfate (CS) induced nephropathy. Therefore, these three salts were investigated in this medium-term bioassay for renal tumorigenesis. Treatment with 5% PDP induced renal calcification with severe nephropathy and promoted the development of preneoplastic lesions, but that with 5% PAS or 0.5% CS did not. To study the effect of alkalization on renal mineralization，animals concomitantly received 5% potassium citrate (PC). The addition of PC to PDP diet reduced the promoting effect on renal tumorigenesis ; also indicated was retardation of renal calcium by histology, serum biochemistry and urinalysis. The promoting effects of PDP and inhibitory effects of PC were correlated to BrdU-labeling indices. Immunohistochemical study was used to examine α₂ᵤ-globulin accumulation ; however, PDP-induced nephropathy did not appear to be related to α₂ᵤ globlin, as evidenced by the negative results. A pathogenesis for renal carcinogenesis is suggested in which nephropathy associated with mineralization enhanced the development of renal cell tumors.