Examination of genotoxicity, toxicity and morphologic alterations in hepatocytes following <i>in vivo</i> or <i>in vitro</i> exposure to methapyrilene

Steinmetz, Karen L.; Tyson, C. Kimerly; Meierhenry, Earl F.; Spalding, Judson W.; Mirsalis, Jon C.

doi:10.1093/carcin/9.6.959

Cited by 57 publications

(18 citation statements)

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“…Acute gavage of 225 mg/kg MP caused hepatic necrosis, increased mitotic figures, and elevated serum enzyme levels characteristic of hepatotoxicity (Lijinsky et al 1980). In a 3-day oral gavage study, 150 mg/kg/day MP resulted in periportal hepatic damage (Steinmetz et al 1988). Previous results also showed that 50 mg/kg/day during 3 days resulted in Environmental Health Perspectives • VOLUME 112 | NUMBER 4 | March 2004…”

Section: Methodsmentioning

confidence: 95%

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.

Waring

Ulrich

Flint

et al. 2004

Environ Health Perspect

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Several studies using microarrays have shown that changes in gene expression provide information about the mechanism of toxicity induced by xenobiotic agents. Nevertheless, the issue of whether gene expression profiles are reproducible across different laboratories remains to be determined. To address this question, several members of the Hepatotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute evaluated the liver gene expression profiles of rats treated with methapyrilene (MP). Animals were treated at one facility, and RNA was distributed to five different sites for gene expression analysis. A preliminary evaluation of the number of modulated genes uncovered striking differences between the five different sites. However, additional data analysis demonstrated that these differences had an effect on the absolute gene expression results but not on the outcome of the study. For all users, unsupervised algorithms showed that gene expression allows the distinction of the high dose of MP from controls and low dose. In addition, the use of a supervised analysis method (support vector machines) made it possible to correctly classify samples. In conclusion, the results show that, despite some variability, robust gene expression changes were consistent between sites. In addition, key expression changes related to the mechanism of MP-induced hepatotoxicity were identified. These results provide critical information regarding the consistency of microarray results across different laboratories and shed light on the strengths and limitations of expression profiling in drug safety analysis. minimal expression of single-cell necrosis with minimal mononuclear infiltrate without associated changes in clinical chemistry parameters (Waring et al. 2001). Thus, in the present study we chose 100 mg/kg/day as the high dose expected to elicit hepatotoxicity. A dose of 10 mg/kg/day was selected as the low dose with the expectation that no hepatotoxic effect would be observed.Male Sprague-Dawley rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA). Rats were 57 days old and weighed 233.4-274.0 g at the start of the treatment. Upon arrival to Abbott Laboratories (Abbott Park, IL), all rats were acclimated for 6 days before treatment began. The two treatment groups comprising four rats each received the test compound at a concentration of 10 or 100 mg/kg, respectively. Animals in the equally sized control group received vehicle only.Rats were dosed once daily by gavage for 7 days. The dose volume was 10 mL/kg. Doses were milligram salt per kilogram per day and were calculated for each rat on the basis of the most recent body weight data available. Rats were fasted overnight after their last treatment, euthanized under halothane anesthesia and submitted for necropsy. Each rat received its last treatment approximately 24 hr before scheduled necropsy.In vivo observations, pathology, and sampling. All rats were observed twice each day during the pretreatment and t...

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Section: Methodsmentioning

confidence: 95%

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.

Waring

Ulrich

Flint

et al. 2004

Environ Health Perspect

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“…Neither WY-14643 nor DEHP produced hyperplasia at the site of skin application in the Tg.AC studies. Methapyrilene is also an hepatocarcinogen but its carcinogenicity is secondary to hepatocyte toxicity and regenerative hyperplasia (30), suggesting that methapyrilene-induced proliferation may be limited The site of application was the shaved dorsal skin in the topical studies and the forestomach in the gavage studies. 2 For the topical studies, chemical CYC was applied in ethanol/water (1:1)…”

Section: Discussionmentioning

confidence: 99%

Tg.AC Genetically Altered Mouse: Assay Working Group Overview of Available Data

Eastin

Mennear²,

Tennant³

et al. 2001

Toxicol Pathol

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In a Government/Industry/Academic partnership to evaluate alternative approaches to carcinogenicity testing, 21 pharmaceutical agents representing a variety of chemical and pharmacological classes and possessing known human and or rodent carcinogenic potential were selected for study in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand the models' limitations and sensitivity in identifying carcinogens. The results of these alternative model studies were reviewed by members of Assay Working Groups (AWG) composed of scientists from government and industry with expertise in toxicology, genetics, statistics, and pathology. The Tg.AC genetically manipulated mouse was one of the models selected for this project based on previous studies indicating that Tg.AC mice seem to respond to topical application of either mutagenic or nonmutagenic carcinogens with papilloma formation at the site of application. This communication describes the results and AWG interpretations of studies conducted on 14 chemicals administered by the topical and oral (gavage and/or diet) routes to Tg.AC genetically manipulated mice. Cyclosporin A, an immunosuppresant human carcinogen, ethinyl estradiol and diethylstilbestrol (human hormone carcinogens) and clofibrate, an hepatocarcinogenic peroxisome proliferator in rodents, were considered clearly positive in the topical studies. In the oral studies, ethinyl estradiol and diethylstilbestrol were negative, cyclosporin was considered equivocal, and results were not available for the clofibrate study. Of the 3 genotoxic human carcinogens (phenacetin, melphalan, and cyclophosphamide), phenacetin was negative by both the topical and oral routes. Melphalan and cyclophosphamide are, respectively, direct and indirect DNA alkylating agents and topical administration of both caused equivocal responses. With the exception of clofibrate, Tg.AC mice did not exhibit tumor responses to the rodent carcinogens that were putative human noncarcinogens, (di(2-ethylhexyl) phthalate, methapyraline HCl, phenobarbital Na, reserpine, sulfamethoxazole or WY-14643, or the nongenotoxic, noncarcinogen, sulfisoxazole) regardless of route of administration. Based on the observed responses in these studies, it was concluded by the AWG that the Tg.AC model was not overly sensitive and possesses utility as an adjunct to the battery of toxicity studies used to establish human carcinogenic risk.

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“…It is now considered to be a rat-specific carcinogen since hepatocellular carcinoma and cholangiocarcinoma were induced by administration of MP at 1000 ppm for 64 weeks, whereas no such findings were observed either in Syrian hamsters, Guinea-pigs, B6C3F1 mice, or humans (Mirsalis, 1987). As for its genotoxicity, the Ames test, DNA addition test, chromosome abnormality test (NTP, 2000) and irregular DNA synthesis test in rat and mouse (Steinmetz et al, 1988) were all negative, whereas the cell transformation assay and L5178Y/TK+/− mouse lymphoma assay were positive (Turner et al, 1987). Based on these observations, hepatocarcinogenicity of MP in rat has been considered to be non-genotoxic, whereas the involvement of its initiation activity cannot be completely excluded (Althaus et al, …”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

et al. 2008

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-The present study was conducted as a model case of the toxicogenomics approach for analyzing toxicological mechanisms and toxicity assessments in the early stage of drug development by comparing with classical toxicology data. Methapyrilene (MP) 100 mg/kg produced obvious histopathological changes in liver of rats by single or repeated dose up to 28 days with significant elevation of ALT and AST. In the middle dose groups (30 mg/kg MP), no apparent changes were noted in blood biochemical data by single dosing or repeated dosing up to one week, and no obvious histopathological changes were observed except a slight hypertrophy in the hepatocytes. Comprehensive gene expression changes were analyzed using Affymetrix GeneChip ® and differentially expressed probe sets were statistically extracted. These contained many genes related to "glutathione metabolism", "apoptosis", "MAPK signaling pathway" and "regulation of cell cycle", which were all thought to be involved in the development of presently observed phenotypes. In the high dose groups, TGP1 scores (developed in our system in order to overview the responsiveness of drugs to multiple marker gene lists) for these categories were markedly increased from the early time point after single dose and kept their high expression throughout the repeated dose period. In the middle dose groups, the increment of the scores were noted not only at the time points when apparent pathological changes emerged, but also at the earlier stage of repeated dosing and even after single dosing. We conclude that toxicogenomics would enable a more sensitive assessment at the earlier time point than classical toxicology evaluation.

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Examination of genotoxicity, toxicity and morphologic alterations in hepatocytes following in vivo or in vitro exposure to methapyrilene

Cited by 57 publications

References 0 publications

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.

Tg.AC Genetically Altered Mouse: Assay Working Group Overview of Available Data

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

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