Use of Precision-Cut Liver Slices to Evaluate Species Differences in 2-Acetylaminofluorene-Induced Unscheduled DNA Synthesis

Lake, Brian G.; Beamand, J.A.; Wield, P.T.; Price, Roger J.

doi:10.1006/taap.1996.0121

Cited by 24 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9 Unfortunately, even with these modifications, necrosis still occurs after 48-72 hours in culture, 10, 18, 19 and metabolic enzyme levels are greatly reduced after 6-72 hours. 17, 20, 21 In addition, rates of drug metabolism and intrinsic clearance were found to be lower in liver slices than in isolated hepatocytes, 22, 23 K m values are usually higher in slices than in isolated hepatocytes, 22 and investigators surmise that a gradient in chemical exposure exists within the tissue slice resulting in not all hepatocytes participating in the metabolism of compounds. 9 …”

Section: Traditional Liver-derived In Vitro Systemsmentioning

confidence: 99%

In vitro models for liver toxicity testing

et al. 2013

View full text Add to dashboard Cite

Over the years, various liver-derived in vitro model systems have been developed to enable investigation of the potential adverse effects of chemicals and drugs. Liver tissue slices, isolated microsomes, perfused liver, immortalized cell lines, and primary hepatocytes have been used extensively. Immortalized cell lines and primary isolated liver cells are currently most widely used in vitro models for liver toxicity testing. Limited throughput, loss of viability, and decreases in liver-specific functionality and gene expression are common shortcomings of these models. Recent developments in the field of in vitro hepatotoxicity include three-dimensional tissue constructs and bioartificial livers, co-cultures of various cell types with hepatocytes, and differentiation of stem cells into hepatic lineage-like cells. In an attempt to provide a more physiological environment for cultured liver cells, some of the novel cell culture systems incorporate fluid flow, micro-circulation, and other forms of organotypic microenvironments. Co-cultures aim to preserve liver-specific morphology and functionality beyond those provided by cultures of pure parenchymal cells. Stem cells, both embryonic- and adult tissue-derived, may provide a limitless supply of hepatocytes from multiple individuals to improve reproducibility and enable testing of the individual-specific toxicity. This review describes various traditional and novel in vitro liver models and provides a perspective on the challenges and opportunities afforded by each individual test system.

show abstract

Section: Traditional Liver-derived In Vitro Systemsmentioning

confidence: 99%

In vitro models for liver toxicity testing

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The toxicity of a number of genotoxins has been assessed in liver slices by detecting UDS with 32 P-postlabeling analysis. For example, Lake et al [32] compared UDS in rats, guinea pigs, male cynomolgus monkeys, and humans after exposure to the mutagens aflatoxin B1 (AFB1), 2-acetylaminofluorene (2-AAF) and 6-aminochrysene (6-AC). UDS was induced by all three compounds in rats, guinea pigs, and humans.…”

Section: Liver Slicesmentioning

confidence: 99%

“…For example, 3MC induced CYP1A1/2 and CYP2B1 and several phase II enzymes including UGT1A6, GSTA1, GSTA2 and GSTM1, all of which have been shown previously to be induced by 3MC in rat hepatocytes. [11,12] -Expensive to maintain -Can only be maintained a few hours Cyclosporine [15] Cadmium, mercury, copper [16] Aromatic amines [18] Acetaminophen [19] Review: [12] Liver slices -Maintains cell-cell and cell-matrix interactions -Contains non-parenchymal cells -Can be used to study zone-specific toxicity [22,25] -Need special equipment for preparation -Can only be maintained a few days AFB1, 2-AAF, 6-AC [32] Carbon tetrachloride [34] Paraquat [35] Cadmium [36] Review: [22] Isolated hepatocytes (on plastic or single layer of collagen)…”

Section: Genomicsmentioning

confidence: 99%

In Vitro Methods to Study Chemically-Induced Hepatotoxicity: A Literature Review

Farkas¹,

Tannenbaum²

2005

CDM

View full text Add to dashboard Cite

Understanding the hepatotoxicity of drugs and chemicals is essential for progress in the pharmaceutical industry, medical science and academic research. The study of hepatotoxicity in vitro is complicated by the difficulty of maintaining hepatocytes in culture due to a lack of understanding of the humoral and matrix requirements of these cells. A variety of in vitro models of the liver have been developed, such as perfused livers, liver slices and three-dimensional perfused bioreactors, but the static cell culture is the most commonly used system. In this review we present the advantages and disadvantages of each system and their roles in the study of hepatotoxicity. We will also discuss how the various culture conditions such as medium and matrix composition affect the systems. The technological advances, which started the fields of genomics, proteomics and metabonomics are playing a very important role in uncovering novel biochemical pathways and markers of toxicity. Several of these studies have focused on hepatotoxicity, particularly on the effects of acetaminophen, carbon tetrachloride and aflatoxin B1. Finally, we will discuss the new field of systems biology, which focuses on interpreting and integrating data from all of the other fields.

show abstract

“…One approach is to compare the effect of a drug in cultured human and animal tissue, providing information about the potential species-specificity of drug-induced adverse effects, otherwise unavailable in the preclinical phase of safety testing. Precisioncut tissue slicing has been a very useful tool in this respect (Smith et al, 1985), and has been increasingly used for interspecies comparisons of toxicity (Fisher et al, 1991(Fisher et al, , 1995Price et al, 1996), metabolism (Steensmae/ al., 1994Connors et al, 1996), liver enzyme induction (Glockner et al, 1995;Heinonen et al, 1996;Lake et al, 1996a), and genotoxicity (Baumann et al, 1996;Beamand et al, 1996;Lake et al, 1996b). Using the same preparative technique in all species, slices are relatively simple to prepare from almost any organ, including important targets of toxicity, such as the liver (Smith et al, 1985), lung (Fisher et al, 1994;Price et al, 1995a,b), and kidney (Ruegg, 1994).…”

Section: European Legislative Mandate (Iain Purchase)mentioning

confidence: 99%