Renal tubular cells

In some human studies where clinical chemistry measurements but no renal biopsies were performed, the only parameter of renal function shown to be affected was an increase in the levels of NAG in the urine. NAG is a lysosomal enzyme present in renal tubular cells that has been shown to be a sensitive indicator of early subclinical renal tubular disease. The mechanism by which lead affects the release of NAG from renal tubular cells is not known, but it is suggested that lead could attach to kidney cell membranes and alter membrane permeability (Chia et al. 1994). 

Fig. 9.1 Schematic diagram depicting drug transporters and their subcellular localization in the human small intestinal enterocyte (A), hepatocyte (B), and renal tubular cell (C).

In an earlier study, there were renal tubular cell adenomas in 5/50 Osbome-Mendel rats receiving doses of 212 mg/kg/day but no tumors in 49 animals receiving 423 mg/kg/day or in 20 vehicle control rats (Weisburger 1977). Despite the lack of tumors, there was a high incidence of nephropathy (18-66%) in exposed male and female rats. 

One of the biological functions of Hp may be to prevent urinary loss of iron as Hb and to prevent blocking of the renal tubular cells by a heavy daily load of reabsorbed Hb. Whether this postulated function is important or not is not known, since no cases of true anhaptoglobin-emia have ever been observed. Another biological function of Hp is to prevent the formation of methemalbumin. 

Information concerning the effects of selenium in man is lacking and it is doubtful whether administration of selenium in man has any effect on the toxicity of mercuric mercury. However, mercury and selenium were found in the cellular lysozomes in renal tubular cells in two patients with inorganic mercury poisoning [143]. 

Chatteijee, S., Trifillis, A. and Regec, A. (1984). Morphological and biochemical effects of gentamicin on cultured human-kidney renal tubular cells. Human Toxicology 3 455. 

Glutamine is exported from the muscle and extracted from blood mainly by the kidneys or the gut hepatic uptake of glutamine is relatively low in comparison. In the renal tubular cells, glutamine is deaminated in the processes of urinary acidification (see Figure 8.11) or used by the intestinal cells as a fuel. 

Kluwe WM, Harrington FW, Cooper SE. 1982. Toxic effects of organohalide compounds on renal tubular cells in vivo and in vitro. J Pharmacol Exp Ther 220 597-603. 

In addition, renal tubular cells contain various proteases for the degradation of proteins and oligopeptides. These enzymes are located predominantly in the lysosomes and micro-somes of these cells, but some have been reported on the brush-border membranes [16]. Degradative enzymes include various endopeptidases, exopeptidases and esterases [17]. 

Apart from drugs directed at hepatocytes and renal tubular cells, in the case of the majority of conventional drugs, it is likely that the drug is not eliminated directly from the target site, and therefore r = 0, which further simplifies Eq. 13.24 to ... 

As shown in Table 2-2, 300 mg/kg/day is the cancer effect level (CEL) for renal tubular cell adenomas in male rats and 600 mg/kg/day is the CEL for hepatocellular carcinomas and hepatoblastomas in mice (NTP 1987). A qj (the upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure) of 6x10 per mg/kg/day has been calculated from the data on renal tumors in rats (Battelle and Crump 1986). The qi for the mouse liver tumor data is 2.4x10 per mg/kg/day (HEAST 1992). These values are currently under review by the EPA (HEAST 1990) and have not been included in the IRIS (1998) database. 

Rat renal tubular cells and hepatocytes Cumulative replicating fraction - Umemura et al. 1998... 

Exposure of rats to p-dichlorobenzene vapor concentrations up to 538 ppm for 2 generations resulted in Fq and Fi adult toxicity, including reduced body weights in both sexes and kidney effects (hyaline droplet neuropathy and renal tubular cell hyperplasia) in males, but... 

Vamvakas S, Muller DA, Dekant W, et al. 1988b. DNA-binding of sulfur-containing metabolites from S-(pentachlorobutadienyl)-L-cysteine in bacteria and isolated renal tubular cells. Drug Metabolic Interact 6 349-358. 

Nephrotoxicity is the most common and the most serious long-term toxicity of amphotericin B administration. This drug reduces glomerular and renal tubular blood flow through a vasoconstrictive effect on afferent renal arterioles, which can lead to destruction of renal tubular cells and disruption of the tubular basement... 

Urinary system-. Groups of 20 male Fischer 344 rats were given 0.05%7V-ethyl-jV-hydroxyethylnitrosamine (EHEN) for two weeks in the diet followed by di(2-ethyl-hexyl) phthalate [purity unspecified] at a concentration of 0 or 1.2% in the diet for 24 weeks. Rats were killed at 27 weeks. Di(2-ethylhexyl) phthalate increased the numbers of rats with renal (tubular) cell tumours (EHEN + di(2-ethylhexyl) phthalate 65% versus 20% for EHEN alone p < 0.01) and the mean number of tumours per kidney (EHEN + di(2-ethylhexyl) phthalate 1.1 versus EHEN alone 0.2,< 0.01) (Kurokawa etal., 1988). 

CELs) in rats due to oral exposure to isophorone. Based on the combined incidences of renal tubular cell tumors and preputial gland tumors, EPA (1986, 1987b) proposed an oral q i of 4.1 x 10 (mg/kg/day) for isophorone, but this analysis is under review by the EPA. 

In the chronic gavage study by NTP (1986), dosed male rats had increased incidences of renal tubular cell hyperplasia, epithelial cell hyperplasia of the renal pelvis, and tubular mineralization. The male rats also had increased incidences of renal tubular cell tumors. The hyperplasia of the tubular cells, therefore, may represent a preneoplastic response (see discussion of cancer below). These proliferative kidney lesions were not observed in male or female mice or in female rats. The mechanism for the induction of proliferative kidney lesions may also be related to a2p-globulin-induced nephropathy (see discussion of cancer below), again raising the question of the relevance of the proliferative kidney lesions in male rats to humans. This issue is presently the subject of scientific investigation. 

Cancer. Increased incidences of relatively rare renal tubular cell adenomas and carcinomas were observed in male rats, but the increases were not statistically significant by the Fisher Exact test or the Cochran-Armitage test (NTP 1986). When adjusted for mortality, however, the increased incidences were significantly different from control in the high-dose males when analyzed by the Lifetable test and significant for dose-related trend by the Lifetable and the Incidental Tumor tests. 

Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae. 

Many putative receptors for anti-dsDNA on the membrane of various cell types have been noted. Some workers found a 30-kDa protein involved in the binding and internalization of [3H]DNA via receptor-mediated endocytosis (B12, B13). Other possible receptors include nucleosomes on human leukocytes (R8), Fc receptors on human T cells (A6), DNA on mouse and human mononuclear cells (06), a 94-kDa protein on several cells lines (J2), DNase-resistant target on human fibroblasts and PK 15 cells (K9), membrane determinant precisely resembling DNA in murine renal tubular cells (Zl), Hp8 on human and murine tubular cells (Z2), ribosomal P protein on rat and human glomerular mesangial cells (S30, S31), brush border myosin 110 kDa on rat hepatoma cells, and a diverse set of membrane proteins on a series of human tumor cell lines (R3). 

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