Induction of peroxisome proliferation in cultured hepatocytes by a series of halogenated acetates

Walgren, Jennie; Jollow, David J.; McMillan, JoEllyn M

doi:10.1016/j.tox.2004.01.007

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…Neither CH nor its metabolite TCA were cytotoxic to rat hepatocytes at concentrations of 3mM/ day for 3 days; these findings are consistent with studies by Bruschi and Bull, (1993); Lash et al, (1995); Walgren et al, (2004 and2005). There was a tendency for MTT activity to be higher than controls for both CH and TCA treated cells, this was not however statistically significant and may just reflect slight differences in plating density, hepatocyte adherence or a compound related alteration in mitochondrial dehydrogenase activity.…”

Section: Discussionsupporting

confidence: 88%

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

et al. 2007

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The industrial solvent trichloroethylene (TCE) and its major metabolites have been shown to cause formic aciduria in male rats. We have examined whether chloral hydrate (CH) and trichloroacetic acid (TCA), known metabolites of TCE, produce an increase in formic acid in vitro in cultures of rat hepatocytes or human renal proximal tubule cells (HRPTC). The metabolism and cytotoxicity of CH was also examined to establish that the cells were metabolically active and not compromised by toxicity. Rat hepatocytes and HRPTC were cultured in serum-free medium and then treated with 0.3-3mM CH for 3 days or 0.03-3mM CH for 10 days respectively and formic acid production, metabolism to trichloroethanol (TCE-OH) and TCA and cytotoxicity determined. No increase in formic acid production in rat hepatocytes or HRPTC exposed to CH was observed over and above that due to chemical degradation, neither was formic acid production observed in rat hepatocytes exposed to TCA. HRPTC metabolised CH to TCE-OH and TCA with a 12-fold greater capacity to form TCE-OH versus TCA. Rat hepatocytes exhibited a 1.6-fold and 3-fold greater capacity than HRPTC to form TCE-OH and TCA respectively. CH and TCA were not cytotoxic to rat hepatocytes at concentrations up to 3mM/day for 3 days. With HRPTC, one sample showed no cytotoxicity to CH at concentrations up to 3mM/day for 10 days, while in another cytotoxicity was seen at 1mM/ day for 3 days. In summary, increased formic acid production was not observed in rat hepatocytes or HRPTC exposed to TCE metabolites, suggesting that the in vivo response cannot be modelled in vitro. CH was toxic to HRPTC at millimolar concentrations/day over 10 days, while glutathione derived metabolites of TCE were toxic at micromolar concentrations/day over 10 days supporting the view that glutathione derived metabolites are likely to be responsible for nephrotoxicity.

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Section: Discussionsupporting

confidence: 88%

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

et al. 2007

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“…Although it is suggested that SODinduced SA dismutation was responsible for H 2 O 2 overproduction, other mechanisms may have also contributed to the overproduction of that species, in response to DCA. For example, DCA was shown to signi¼cantly induce peroxisome proliferation in cultured hepatocytes (Walgren et al, 2004), and the peroxisomes are known to be sources of H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate‐induced modulation of cellular antioxidant enzyme activities and glutathione level in the J774A.1 cells

Hassoun

Mehta

2008

J of Applied Toxicology

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Dichloroacetate (DCA) is used for different medical and industrial purposes and has been found to be a toxic by-product produced during the process of water chlorination. The DCA effects on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities and glutathione (GSH) level were assessed and correlated with each other and also with cellular viabilities in J774A.1 macrophage cells. A concentration of 24 mm of DCA resulted in time-dependent decreases in cellular viability and glutathione level, and time-dependent increases in SOD activity when incubated with the cells for 24-48 h. DCA also resulted in significant increases in CAT and GSH-Px activities of the viable cells when incubated with the cells for 36 and 48 h. The changes in antioxidant enzyme activities and GSH levels were found to be strongly correlated with each other, and with cellular viabilities at different time points. While GSH did not result in any significant effects when added to the cells at concentrations ranging between 15 and 60 nmol ml(-1), it resulted in concentration-dependent increases in cellular viability when added to the DCA-treated cells, with maximal effects achieved at 45-60 nmol GSH ml(-1). However, cellular viability of the GSH + DCA treated cells remained below that of the control. Since viable cells from the DCA-treated cultures displayed significantly higher antioxidant enzyme activities compared with the control, it is concluded that those increases may have contributed to the cellular protection against DCA-induced cell death. Also, glutathione depletion has a major contribution to the observed cellular death induced by DCA.

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“…Next, the evaluation of the different evidence streams for individual HAAs was used to inform an assessment (read-across approach) to determine if any patterns of toxicity and carcinogenicity were related to structural classes of HAAs (see Figure 3, Step B, top). Several mechanistic studies that tested three or more HAAs concurrently in the same test system were particularly informative for the read-across approach because they helped identify data trends by directly comparing the toxicokinetics, chemical properties, and/or toxic effects across multiple HAAs (Larson and Bull 1992;Austin et al 1996;Schultz et al 1999;Kargalioglu et al 2002;Walgren et al 2004;Plewa et al 2010;Zhang et al 2010;Stalter et al 2016;Zhang et al 2016). Carcinogenicity potency estimates for the HAAs that induced cancer in experimental Figure 3.…”

Section: Cancer Hazard Evaluationmentioning

confidence: 99%

New Perspectives for Cancer Hazard Evaluation by the Report on Carcinogens: A Case Study Using Read-Across Methods in the Evaluation of Haloacetic Acids Found as Water Disinfection By-Products

Atwood

Lunn

Garner

et al. 2019

Environ Health Perspect

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BACKGROUND: Due to the large number of chemicals not yet tested for carcinogenicity but to which people are exposed, the limited number of human and animal cancer studies conducted each year, and the frequent need for a timely response, mechanistic data are playing an increasingly important role in carcinogen hazard identification. OBJECTIVES: To provide a targeted approach to identify relevant mechanistic data in our cancer evaluation of haloacetic acids (HAAs), we used several approaches including systematic review, the 10 key characteristics of carcinogens (KCs), and read-across methods. Our objective in this commentary is to discuss the strengths, limitations, and challenges of these approaches in a cancer hazard assessment. METHODS: A cancer hazard assessment for 13 HAAs found as water disinfection by-products was conducted. Literature searches for mechanistic studies focused on the KCs and individual HAAs. Studies were screened for relevance and categorized by KCs and other relevant data, including chemical properties, toxicokinetics, and biological effects other than KCs. Mechanistic data were organized using the KCs, and strength of evidence was evaluated; this information informed potential modes of action (MOAs) and read-across-like approaches. Three read-across options were considered: evaluating HAAs as a class, as subclass(es), or as individual HAAs (analog approach). DISCUSSION: Because of data limitations and uncertainties, listing as a class or subclass(es) was ruled out, and an analog approach was used. Two brominated HAAs were identified as target (untested) chemicals based on their metabolism and similarity to source (tested) chemicals. In addition, four HAAs with animal cancer data had sufficient evidence for potential listing in the Report on Carcinogens (RoC). This is the first time that the KCs and other relevant data, in combination with read-across principles, were used to support a recommendation to list chemicals in the RoC that did not have animal cancer data.

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Induction of peroxisome proliferation in cultured hepatocytes by a series of halogenated acetates

Cited by 10 publications

References 39 publications

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

Dichloroacetate‐induced modulation of cellular antioxidant enzyme activities and glutathione level in the J774A.1 cells

New Perspectives for Cancer Hazard Evaluation by the Report on Carcinogens: A Case Study Using Read-Across Methods in the Evaluation of Haloacetic Acids Found as Water Disinfection By-Products

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