In vitro nephrotoxicity

Sina, J.E, Bean, C.L., Noble, C. and Bradley, M.O. (1985). An in vitro nephrotoxicity assay utilizing proximal tubule suspensions from rabbit kidney. In In Vitro Toxicology, Vol 3. Mary Ann Liebert, New York, pp. 683-693. 

Jaffe DR, Hassall CD, Brendel K. 1983. In wVoand in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J Toxicol Environ Health 11 857-867. 

In vitro nephrotoxicity study variables. Cell culture medium Oxygen... 

Renal cell cultures, which retain adequate renal cellular functions known to interact with xenobiotics or drugs, have the advantage of providing an experimental model that is not influenced by higher-order regulatory systems. Non cell culture based in vitro nephrotoxicity systems have been reviewed elsewhere [15]. 

Cell tines offer several advantages over primary cell cultures, such as an unlimited life-span and the lack of time-consuming isolation procedures. Additionally once established, they are often more stable than primary cells which are usually in a continuous state of de-differentiation. Thus, the majority of in vitro nephrotoxicity studies have been performed on renal epithelial cell tines. In normal somatic cells, telomeres, the tandemly repeated hexamers at the end of mammalian chromosomes, act as the cellular replicative clock [43] and shorten at each cell division. Once telomeres have exceeded a certain critical length, the so called "Hayflick limit" [44], the cell enters replicative senescence and no longer proliferates. Until recently the most widely used renal cell tines were those which arose from spontaneously acquired immortalization in culture. These cell tines include LLC-PK (Hampshire pig) [45,46], JTC-12 (cynomolgus monkey) [47] and OK (American opossum) [48] cells, which exhibit biochemical and antigenic characteristics suggestive of proximal... 

Jennings P (2001) Novel approaches for in vitro nephrotoxicity testing. PhD thesis, University College Dublin Library... 

Nevertheless, the majority of in vitro nephrotoxicity studies have been performed on permanent or continuous renal epithelial cell lines. 

The precise knowledge of the physiological and biochemical properties of the in vitro models used and their monitoring during culture is mandatory for the selection of biologically relevant endpoints for in vitro nephrotoxicity studies. Marked alterations of these prede-... 

Duff T, Carter S, Feldman G, McEwan G, PfaUer W, Rhodes P, Ryan M, Hawksworth G. 2002. Transepithehal resistance and inulin permeability as endpoints in in vitro nephrotoxicity testing. Ahern LabAnim 30(Suppl 2) 53-59. 

In experimental animals and in vitro, DHBs show a variety of biological effects including binding of metaboHtes to various proteins. Clastogenic effects have been observed in vitro and in some in vivo studies with the three compounds. No reproductive effects have been shown by conventional studies with either hydroquinone, catechol, or resorcinol (122). Hydroquinone has been shown to induce nephrotoxicity and kidney tumors at very high doses in some strains of rat (123) catechol induces glandular stomach tumors at very high dose (124). Repeated dermal appHcation of resorcinol did not induce cancer formation (125). 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

Xylan-based microparticles were also evaluated regarding their in vitro toxicity. In fact, cross-liked (CLM) and spray-dried microparticles (SDM) based on xylan and ESIOO were produced in order to carry UA and avoid its side effects, namely hepatotoxicity and nephrotoxicity. Additionally, CLM and SDM dispersions at concentrations of 50, 125, 250, and 500 pg/ml were placed in contact with human embiyonic Ixmg fibroblasts (MRC-5 cells)... 

Kacew, S. and Hirsch, G.H. (1981). Evaluation of nephrotoxicity of various compounds by means of in vitro techniques and comparison to in vivo methods. In Toxicology of the Kidney (Hook, J.B., Ed.). Raven Press, New York, pp. 77-98. 

Smith, J.H. and Hook, J.B. (1983). Mechanism of chloroform nephrotoxicity. II. In vitro evidence for renal metabolism of chloroform in mice. Toxicol. Appl. Pharmacol. 70 480-485. 

Williams, P.D. (1989). The application of renal cells in culture in studying drug-induced nephrotoxicity. In Vitro 25 800-805. 

Williams, P.D., Hottendorf, G.H. and Bennett, D.B. (1986a). Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides. J. Pharmacol. Exp. Ther. 237 919-925. Williams, P.D., Laska, D.A. and Hottendorf, G.H. (1986b). Comparative toxicity of aminoglycoside antibiotics in cell cultures derived from human and pig kidney. In Vitro Toxicol. 1 23-32. 

Fig. 11.18. Cyclization-elimination reactions in the in vitro and in vivo metabolism of nephrotoxic 2-haloethylamines (11.133). Aziridine (11.134) formation is probably a reaction of tox-ification, whereas oxazolidin-2-one (11.136) is clearly a reaction of detoxification [155][156].

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

Bailie MB, Smith JH, Newton JF, et al. 1984. Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys. Toxicol Appl Pharmacol 74 285-292. 

Charbonneau M, Strasser J, Lock EA, et al. 1989a. 1,4-Dichlorobenzene-induced nephrotoxicity Similarity with unleaded gasoline (UG)-induced renal effects. In Bach P, Lock EA, eds. Nephrotoxicity In vitro to in vivo. Animals to man. New York, NY Plenum Press, 557-562. 

Thus, the nephrotoxicity and covalent binding of metabolites to renal protein can be reduced by treating animals with the organic acid probenecid, which competes with the cysteine conjugate for the active uptake system. The cytotoxicity of the GSH conjugate of HCBD in vitro is reduced by inhibitors of (3-glutamyltransferase and (3-lyase, indicating that both these enzymes are essential for the toxicity. 

Boogaard, P.J., Mulder, G.J. Nagelkerke, J.F. (1989) Isolated proximal tubular cells from rat kidney as an in vitro model for studies on nephrotoxicity. II. a-Methylglucose uptake as a sensitive parameter for mechanistic studies of acute toxicity by xenobiotics. Toxicol, appl. Pharmacol., 101, 144-157... 

Trevisan, A., Meneghetti, P, Maso, S. Troso, O. (1993) In vitro mechanisms of 1,2-dichloropropane nephrotoxicity using the renal cortical slice model. Hum. exp. Toxicol., 12,117-121 von der Hude, W., Scheutwinkel, M., Gramlich, U., Fissler, B. Easier, A. (1987) Genotoxicity of three-carbon compounds evaluated in the SCE test in vitro. Environ. Mutagen., 9.401-410... 

---