Effects of methrpyrilene measured in mitochondria isolated from naive and methapyrilene-treated rat and mouse hepatocytes

Copple, Deborah M.; Rush, Glenn F.; Richardson, Frank C.

doi:10.1016/0041-008x(92)90138-i

Cited by 8 publications

(3 citation statements)

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“…Our data is consistent with other reports that suggest an involvement of mitochondrial dysfunction and perturbation of Ca ++ homeostasis in the observed MP associated hepatocellular necrosis (13,44). Treatment of rats with MP has been shown to form reactive metabolites that covalently bind specifically to mitochondrial proteins (50) and damage to the inner mitochondrial membrane has been proposed to play a significant role in MP toxicity (51,60).…”

Section: Discussionsupporting

confidence: 93%

“…In this study, not only were gene expression profiles of toxicant response demonstrated as a surrogate for toxicity classification, but their content was also useful in corroborating microscopic observations mechanistically (Table 4). In addition, gene expression alterations were consistent with events such as mitochondrial dysfunction in response to MP, which requires ultrastructure analyses (13,47,48) and cannot be discerned clearly using classical histopathological studies.…”

Section: Discussionmentioning

confidence: 86%

“…In addition, gene expression alterations were consistent with events such as mitochondrial dysfunction in response to MP, which requires ultrastructure analyses (13,47,48) and cannot be discerned clearly using classical histopathological studies.…”

Section: Hamadeh Et Al Toxicologic Pathologymentioning

confidence: 86%

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Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

et al. 2002

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Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression patterns, and 3) to gain insight into mechanism(s) of methapyrilene hepatotoxicity. Large-scale differential gene expression levels associated with the exposure of male Sprague-Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/kg/day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low-dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes.Keywords. Toxicogenomics; gene expression; methapyrilene; toxicity classification; rat liver; histopathology; phenotypic anchorage; hepatotoxicity.INTRODUCTION Methapyrilene (MP) is an antihistaminic compound once used as a popular over-the-counter sleep-aid component and also used in cold and allergy medications. It was found to induce hepatocellular carcinomas and cholangiocarcinomas in rats (20, 31, 33) and was subsequently withdrawn from the market. However, its carcinogenicity appears to be species-specific because no evidence has been found of MPassociated carcinogenesis in mice (3), guinea pigs, hamsters (32), or humans (36).MP was negative in the DNA adduct formation assay (8, 9, 34) and has not been found to be mutagenic with the Ames assay or other mutation assays (7, 38). Furthermore, MP did not induce unscheduled DNA synthesis (4) and did not cause sister-chromatid exchange (24). These data are consistent with the hypothesis that MP is carcinogenic in rats via nonmutagenic mechanisms (36,54). MP is extensively metabolized by the liver (29, 53), and phase I metabolism plays a major role in its toxicity because cytochrome P450 inhibitors afford protection from the toxicity of MP (43). The oxidative potential of methapyrilene and/or metabolites and increased cellular proliferation have been proposed to play a central role in the observed toxicity (9,45,49). Bile duct cannulation of MP treated rats affords protection from MP hepatic toxicity suggesting that enterohepatic recirculation of glucuronidated metabolites plays a role in MP toxicity (45). In humans, methapyrilene has a very short half-life, a relatively high apparent volume of distribution, and total

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 86%

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Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

et al. 2002

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Hepatotoxicity

Hinton

Grasso

Marrs

2009

General, Applied and Systems Toxicology

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The liver has many physiological roles and is a key organ in detoxication. Furthermore, the liver is affected by a very large number of xenobiotics. The liver also has an immense capacity for self‐repair, so that the many abnormalities of structure or function in the liver reverse rapidly on cessation of xenobiotic exposure. Nevertheless the liver's defences can be overwhelmed. Acute liver failure can be caused by many compounds e.g. paracetamol (acetaminophen), while repeated liver damage, for example from ethanol, may lead to cirrhosis. While primary liver cancer is rare in Western Europe and North America, it is common in other parts of the world such as sub‐Saharan Africa, alcohol and aflatoxins being amongst the aetiological factors. Non‐dose‐dependent adverse effects on the liver are common with many classes of drug and may be sufficiently severe to require cessation of treatment. In the regulatory context it is important to recognize the difference between adaptive and toxic effects.

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Comparisons of protein changes in human and rodent hepatocytes induced by the rat‐specific carcinogen, methapyrilene

et al. 1993

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There is a growing concern that the rodent bioassay may not always serve as an appropriate model to assess the carcinogenic risk for humans exposed to certain compounds. Mechanistic research that examines the effects of a compound in rodent and man could help in the interpretation of bioassay results. This paper reports a novel use of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) technology to assess similarities and differences in the response of rodents and humans to the rat-specific hepatocarcinogen, methapyrilene (MP). A sequential examination of rodent and human hepatic proteins was conducted following in vivo exposure of rats and mice and in vitro exposure of rat, mouse, and human hepatocytes to MP. Results showed that covalent modifications observed in rats and mice in vivo were duplicated both qualitatively and quantitatively in the corresponding in vitro systems and that these modifications correlated with carcinogenic susceptibility. Covalent modifications in human hepatocytes were minimal despite exposure to concentrations of MP that were 6-fold higher than those used in rodent hepatocytes. These studies suggest that in the case of MP the rat is not the most appropriate model for assessing the human situation. Furthermore, these data show that in vitro-in vivo comparisons based on 2-D PAGE may provide adjunctive information for extrapolating rodent toxicity/bioassay results to human risk assessment.

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Effects of methrpyrilene measured in mitochondria isolated from naive and methapyrilene-treated rat and mouse hepatocytes

Cited by 8 publications

References 20 publications

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

Hepatotoxicity

Comparisons of protein changes in human and rodent hepatocytes induced by the rat‐specific carcinogen, methapyrilene

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