Effects of methapyrilene on DNA synthesis in mice and rats following continuous dietary exposure

Richardson, Frank C.; Copple, Deborah M.; Eacho, Patrick I.

doi:10.1093/carcin/13.12.2453

Cited by 18 publications

(12 citation statements)

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“…Whereas lipid peroxidation was a common response to MP and 2 noncarcinogenic analogs methafurylene and thenyldiamine, the hepatocellular labeling indexes were considerably increased in MP-treated rats as opposed to a no-change-effect in this parameter in rats treated with pyrilamine, a noncarcinogenic analog of MP. Moreover, this phenomenon was not observed in MP-treated mice, where MP toxicity and carcinogenicity are absent (49), thus further supporting the link between cell proliferation and carcinogenesis of MP. Interestingly, we observed the induction of a subset 480 HAMADEH ET AL TOXICOLOGIC PATHOLOGY FIGURE 6.-A schematic diagram summarizing the major findings of this report showing that in the dose-time universe of methapyrilene exposure, both histopathological and gene expression evaluations were able to classify the toxicity incurred in livers of exposed animals.…”

Section: Hamadeh Et Al Toxicologic Pathologymentioning

confidence: 66%

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: Hamadeh Et Al Toxicologic Pathologymentioning

confidence: 66%

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

et al. 2002

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“…However, the results indicate that FIAU is not rapidly removed from genomic DNA, suggesting that removal does not occur via an active repair mechanism. FIAU-DNA concentrations could be reduced through hepatocyte turnover, which has been reported to range from 0.3-1.5% per day in rats and mice (15)(16)(17). Data on hepatocyte turnover in dogs is not available.…”

Section: Methodsmentioning

confidence: 99%

Fialuridine accumulates in DNA of dogs, monkeys, and rats following long-term oral administration.

Richardson

Engelhardt

Bowsher

1994

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of the antiviral nucleoside analogue fraluridine (FIAU; 1-(2'-deoxy-2'-fluoro-P-D-arab- In part because of the lactic acidosis observed in the clinical trials, it has been proposed that FIAU may selectively affect mitochondrial function. Depletion of muscle mitochondrial DNA (mtDNA) has been observed with dideoxycytidine (ddC) (6) and 3'-azido-3'-deoxythymidine (AZT) (7) and has been suggested as a possible mechanism for the delayed toxicity of FIAU. Unlike AZT and ddC, however, FIAU has a free 3'-OH, which in theory permits internal incorporation into full-length DNA. Acute studies have shown that FIAU is incorporated into the DNA of (10). While the biological consequences of FIAU incorporation into DNA remain unclear, in vitro studies with 9-Darabinofuranosyl-2-fluoroadenine (F-ara-A) (11) and 1-Darabinofuranosylcytosine (araC) (12) have correlated toxicity with incorporation into genomic DNA, suggesting that incorporation of FIAU into genomic DNA could also lead to cytotoxicity. Since clinical deterioration only occurred after long durations of exposure, it could be hypothesized that not simply incorporation but net accumulation of FIAU in DNA could be critical to the delayed toxicity of FIAU. Therefore, studies were conducted to measure FIAU accumulation in DNA of rats, monkeys, and dogs following long-term oral administration.In the past, measuring FIAU incorporation into DNA was done by using standard radiolabeling techniques and only in acute pulse-dose studies (9, 10). These techniques are not amenable to assessing FIAU accumulation in DNA following long-term dosing regimens (90 days) and in larger species (dogs and monkeys) because of the large amounts of radioactivity required and the safety hazards associated with administering large quantities ofradioactivity to animals over extended periods of time. Recently, however, the development of a sensitive radioimmunoassay (RIA) for use on biological fluids (13) has made it feasible to measure concentrations of FIAU-DNA under such conditions. MATERIALS AND METHODSAll DNA samples were obtained from animals used in studies conducted in the Toxicology Division of Eli Lilly and Company. In this manuscript, full descriptions of all toxicology studies have not been provided; complete reports will be published elsewhere. Only information necessary to the interpretation of FIAU-DNA incorporation has been provided. Since toxicological evaluation was the primary purpose of these studies, the doses for each species vary and are

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“…In order to conserve the use of animals, animal tissues previously used in cell replication studies (16) were also used for these 2-D PAGE studies. Therefore, the methodology for dosing of animals includes all techniques used for both studies, although results from only the 2-D PAGE analysis are listed in this article.…”

Section: Animal Dosing and Tissue Preparationmentioning

confidence: 99%

“…Instead MP appears to operate synergistically with the initiator DEN (14). MP may induce liver cancer by increasing hepatocyte proliferation over an extended period of time (15,16).…”

Section: Introductionmentioning

confidence: 99%

Dose-responses in rat hepatic protein modification and expression following exposure to the rat hepatocarcinogen methapyrilene

Richardson¹,

Horn²,

Anderson

1994

Carcinogenesis

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Dose-related effects of methapyrilene (MP) on protein modification and expression were examined using two-dimensional gel electrophoresis (2-D PAGE) coupled with computer analysis. Methapyrilene was administered ad libitum at doses of 0, 62.5, 125, 250 and 1000 p.p.m. to male F-344 rats for 12 weeks beginning at 8 weeks of age. Following treatment, livers were removed and frozen for 2-D PAGE analysis. Separation of hepatic proteins was conducted using ISO-DALT technology. Changes in abundance and modification of hepatic proteins were determined using the Kepler software package. Covalent modifications of three specific mitochondrial proteins were quantified using a charge modification index. Dose-response relationships were analyzed using Tukey's trend test. Results demonstrated that covalent modification of the three mitochondrial proteins was linearly related to dose and that a dose effect could be found at all dose levels in 2 out of 3 proteins. Two forms of change in protein expression were observed: (i) a dose-dependent change with effects at all doses and (ii) a change only at the toxic dose of 1000 p.p.m. MP. These results demonstrate a molecular effect of MP at doses that do not produce cellular responses including toxicity or increases in cell replication suggesting that these specific mitochondrial modifications are molecular dosimeters but are probably not direct factors and/or sufficient factors in carcinogenesis. This study also demonstrates the potential use of 2-D PAGE electrophoresis to delineate the effect of dose on expression of specific proteins.

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Effects of methapyrilene on DNA synthesis in mice and rats following continuous dietary exposure

Cited by 18 publications

References 0 publications

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

Fialuridine accumulates in DNA of dogs, monkeys, and rats following long-term oral administration.

Dose-responses in rat hepatic protein modification and expression following exposure to the rat hepatocarcinogen methapyrilene

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