Interest and limits of human tissue and cell use in pharmacotoxicology

Potier, Marie Claude; Lakhdar, B.; Merlet, D.; Cambar, J.

doi:10.1007/bf00756514

Cited by 4 publications

(3 citation statements)

References 12 publications

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“…Other possibilities include using animal cells that are transfected to express human genes and proteins. For example, various cell lines—such as V79, CHO, COS-7, NIH3T3, and HEPG2—have been transfected with complementary DNA (cDNA, DNA synthesized from mature mRNA) coding for human enzymes and used in mutagenesis and drug-metabolism studies (Potier et al, 1995). Individual enzymes have also been stably expressed to identify the major human isoenzymes, such as cytochromes P-450 and UDP-glucuronosyltransferases, responsible for the metabolism of potential therapeutic and environmental agents.…”

Section: Tools and Technologiesmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

816

475

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With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

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Section: Tools and Technologiesmentioning

confidence: 99%

Toxicity Testing in the 21st Century: A Vision and a Strategy

Krewski

Acosta

Andersen

et al. 2010

Journal of Toxicology and Environmental Health, Part B

816

475

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“…Numerous studies performed in our laboratory established that the two in vitro glomerular models can be considered useful tools in order to demonstrate the vasoactive potential of some nephrotoxic agents reducing dramatically renal hemodynamics and glomerular filtration rate [17, 18, 19]. The contractile ability of the glomerulus seems to be a major determinant of renal blood flow and ultrafiltration surface regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in a worrying way, metals emerge as a serious cause of environment damage, and their environmental levels have risen steadily [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. These results serve to elucidate the role of cadmium, in the form of simple salts, in the impairment of glomerular structures, especially mesangial cells, and do not focus attention solely on the tubular dysfunctions already described [35].…”

Section: Discussionmentioning

confidence: 99%

Cadmium Nephrotoxicity Assessed in Isolated Rat Glomeruli and Cultured Mesangial Cells: Evidence for Contraction of Glomerular Cells

Barrouillet¹,

Potier²,

Cambar³

1999

Nephron Exp Nephrol

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Cadmium (Cd), an important pollutant, causes severe damage at the renal tubular level. Numerous previous studies have focused upon Cd tubular nephrotoxicity. The present study of Cd-induced glomerular damage examined the vasoactive effect of Cd in freshly isolated glomeruli and mesangial cells. Glomeruli were isolated by passing rat renal cortex pulp through calibrated sieves followed by culture for outgrowth of cells. Quantitative evaluation of glomerular and cellular contractions was performed by morphometric measurement of the area with an automatized image analyzer following different incubation times with Hanks’ balanced salt solution or Cd²⁺. Each glomerulus or mesangial cell served as its own control. Cd lethality was measured with microassay methods (neutral red, MTT uptake, and lactate dehydrogenase release), allowing the determination of an IC₅₀. This ranged from 35 to 60 μM. CdCl₂ induced a time-dependent contractile effect on isolated glomeruli; planar surface area decreases were 6.9% (1 μM), 7.5% (0.1 μM), and 7% (0.01 μM). The decrease started as soon as Cd was in contact with glomeruli and ended 40 min later: T5 (2%), T10 (3.5%), T20 (4.2%), T30 (6.3%), T40 (7%). Cell size reduction was 19% (1 μM), 14% (0.1 μM), and 18% (0.01 μM) and was also time-dependent. To confirm that contractile events occurred during the cell shape changes, examination of the mesangial α-actin network was performed concurrently. These results indicate that Cd contracts glomerular structures. This may, in part, explain the reduction in glomerular filtration seen in Cd nephrotoxicity.

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