PMID- 8314463
OWN - NLM
STAT- MEDLINE
DCOM- 19930729
LR  - 20190909
IS  - 0272-0590 (Print)
IS  - 0272-0590 (Linking)
VI  - 20
IP  - 4
DP  - 1993 May
TI  - An in vitro model of cyclosporine-induced nephrotoxicity.
PG  - 486-95
AB  - The predominant hypothesis for cyclosporine-induced acute renal failure is 
      postulated to be prerenal vasoconstriction with concomitant hemodynamic changes; 
      an alternate hypothesis, however, may be that cyclosporine (CsA) affects 
      intrarenal processes, i.e., direct renal parenchymal cell injury. However, 
      reports on this direct effect of CsA on renal parenchymal cells are 
      contradictory. Therefore, the purpose of this study was to address whether CsA is 
      directly toxic to renal parenchymal cells in a primary culture system of rat 
      renal cortical epithelial cells. The cytotoxicity of Sandimmune, the commercial 
      form of CsA in a polyoxyethylated castor oil vehicle (Cremophor), CsA without 
      vehicle, and the Cremophor vehicle was assessed by plasma membrane integrity 
      (lactate dehydrogenase leakage), mitochondrial metabolic activity 
      [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction], and 
      gross morphology (phase-contrast microscopy). The cytotoxicity of Sandimmune was 
      also assessed by lysosomal activity (neutral red uptake), by proximal tubular 
      enzyme activity (alkaline phosphatase), and by three fluorescent probes using a 
      multiwell scanner. The three fluorescent probes were propidium iodide which 
      stains nuclei of nonviable cells; bis-carboxyethyl-carboxyfluorescein which is 
      retained by viable cells; and rhodamine 123, which assesses mitochondrial 
      membrane potential. The results of this study demonstrated that Sandimmune caused 
      dose- (10, 25, and 50 microM) and time- (12, 24, and 48 hr) dependent 
      cytotoxicity, while Cremophor caused cytotoxicity only at high concentrations and 
      long incubations. We conclude that (1) CsA is directly toxic to renal parenchymal 
      cells in vitro and this system potentially represents a sensitive model for 
      further mechanistic studies; (2) CsA plus vehicle (Sandimmune) was more cytotoxic 
      to renal cells than CsA alone (without the polyoxyethylated castor oil vehicle).
FAU - Jiang, T
AU  - Jiang T
AD  - Division of Pharmacology & Toxicology, College of Pharmacy, University of Texas, 
      Austin 78712.
FAU - Acosta, D
AU  - Acosta D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Fundam Appl Toxicol
JT  - Fundamental and applied toxicology : official journal of the Society of 
      Toxicology
JID - 8200838
RN  - 0 (Fluoresceins)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Pharmaceutical Vehicles)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - 261QK3SSBH (Neutral Red)
RN  - 36015-30-2 (Propidium)
RN  - 39279-69-1 (cremophor)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 85138-49-4 (2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
RN  - EUY85H477I (thiazolyl blue)
SB  - IM
MH  - Alkaline Phosphatase/metabolism
MH  - Animals
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cyclosporine/*toxicity
MH  - Fluoresceins
MH  - Fluorescent Dyes
MH  - Kidney Cortex/cytology/drug effects/enzymology
MH  - Kidney Diseases/*chemically induced/enzymology/pathology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Mitochondria/drug effects
MH  - Neutral Red
MH  - Pharmaceutical Vehicles/toxicity
MH  - Polyethylene Glycols/toxicity
MH  - Propidium
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tetrazolium Salts
MH  - Thiazoles
EDAT- 1993/05/01 00:00
MHDA- 1993/05/01 00:01
CRDT- 1993/05/01 00:00
PHST- 1993/05/01 00:00 [pubmed]
PHST- 1993/05/01 00:01 [medline]
PHST- 1993/05/01 00:00 [entrez]
AID - S0272059083710596 [pii]
AID - 10.1006/faat.1993.1059 [doi]
PST - ppublish
SO  - Fundam Appl Toxicol. 1993 May;20(4):486-95. doi: 10.1006/faat.1993.1059.