Species differences in the metabolism and macromolecular binding of methapyrilene: a comparison of rat, mouse and hamster

Lampe, Mary; Kammerer, R. Craig

doi:10.3109/00498259009046626

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…MP has been reported to bind to DNA in vitro (9) but binding to DNA in vivo was not found (10,11). However, studies have shown that MP or a metabolite covalently binds to hepatic proteins (12) and is localized to the mitochondria (13). MP does not appear to be an initiator of carcinogenesis but also does not appear to be a strict promoter.…”

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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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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“…Note that although several compounds are known to undergo metabolic activation at a thiophene ring (Kalgutkar et al, 2005), no metabolites of MP arising from oxidation of this moiety have been described previously (Kammerer and Schmitz, 1986;Singer et al, 1987). Differences between the metabolism of MP in rats and mice are both qualitative and quantitative (Lampe and Kammerer, 1990), but they have not provided a rigorously tested metabolic explanation of the greater susceptibility of rat hepatocytes (Kelly et al, 1992). Although metabolites of MP have been postulated as causal to the hepatotoxicity of the drug (Singer et al, 1987;Kelly et al, 1992;Ratra et al, 1998b), this toxicity has not been linked experimentally with either metabolic activation, as represented by irreversible drug binding, or any stable metabolites of MP derived from reactive intermediates.…”

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confidence: 99%

“…Iminium ions, iminoquinones, epoxides, and aldehyde species have all been suggested as reactive metabolites of MP (Ziegler et al, 1981;Singer et al, 1987;Lampe and Kammerer, 1990;Kelly et al, 1992). Two iminium ions generated by rabbit liver microsomes were trapped with cyanide, and one stable adduct, N-(cyanomethyl)normethapyrilene, was identified (Ziegler et al, 1981).…”

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confidence: 99%

Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Graham¹,

Walsh²,

Hirst³

et al. 2008

J Pharmacol Exp Ther

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Methapyrilene (MP), a 2-thiophene H 1 -receptor antagonist, is a model toxicant in the genomic and proteomic analyses of hepatotoxicity. In rats, it causes an unusual periportal necrosis that is hypothetically attributed to chemically reactive and cytotoxic metabolites. We have characterized the bioactivation of MP by hepatic microsomes and primary rat hepatocytes, and we established a possible causal linkage with cytotoxicity. Methapyrilene tritiated at C-2 of the diaminoethane moiety ([ 3 H]MP) was metabolized via an NADPH-dependent pathway to intermediates that combined irreversibly with microsomes (rat Ͼ mouse Ϸ human). This binding was attenuated by the cytochrome P450 (P450) inhibitor 1-aminobenzotriazole and thiols but not by trapping agents for iminium ions and aldehydes. Reactive intermediates were trapped as thioether adducts of monooxygenated MP. Mass spectrometric and hydrogen/deuterium exchange analysis of the glutathione adduct produced by rat liver microsomes indicated that the metabolite was most probably a thioether of MP S-oxide substituted in the thiophene ring. The glutathione adduct was formed by rat hepatocytes and eliminated in bile by rats administered [ 3 H]MP intravenously. MP produced concentration-and time-dependent cytotoxicity, depleted glutathione, and underwent irreversible binding to the hepatocytes before a significant increase in cell damage was observed. P450 inhibitors reduced turnover of the drug, production of the glutathione adduct, irreversible binding, and cytotoxicity but inhibited glutathione depletion selectively. MP underwent lesser turnover and bioactivation in mouse hepatocytes and was not cytotoxic. Analogs with phenyl and p-methoxyphenyl rings were much less hepatocytotoxic than MP. Hepatotoxicity in rats was diminished by predosing with 1-aminobenzotriazole. For the first time, a thiophene ring substituent is identified as a bioactivation-dependent toxicophore in hepatocytes. Fig. 1], a 2-thiophene H 1 -receptor antagonist, was not associated with hepatotoxicity in humans, but it causes unusual dose-dependent periportal damage in adult male rats (Graichen et al., 1985;Ratra et al., 1998a;Ratra et al., 2000). Typical hepatotoxic regimens (150 -300 mg/kg/day ϫ 3) produce a mild to moderate injury characterized by hepatocellular necrosis, bile duct proliferation, and inflammatory cell infiltration. MP is also toxic to isolated rat hepatocytes (McQueen and Williams, 1982;Ratra et al., 1998b), which are reported to be more susceptible than mouse hepatocytes (Kelly et al., 1992).MP has come to be regarded as a model investigatory compound among drug hepatotoxicants, and it is used fre- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.135483.ABBREVIATIONS: MP, methapyrilene; P450, cytochrome P450; tGSH, total glutathione (GSH plus glutathione disulfide); MeOD, monodeuteromethanol; HPLC, high-performance liquid chromatography; [ 3 H]MP, methapyrilene tritiated at C-2 of the diaminoethane moie...

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“…While many metabolites of methapyrilene have been identified, the metabolite(s) responsible for hepatic damage in rats remains elusive. Species differences in the metabolism of methapyrilene seem largely quantitative rather than qualitative (Kammerer and Schmitz, 1987;Lampe and Kammerer, 1990). It is plausible, therefore, that the species differences in methapyrilene-induced hepatotoxicity may be explained by differences in the metabolic activation or detoxication pathways.…”

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Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

Ratra¹

1998

Toxicological Sciences

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The mechanisms by which the antihistamine drug methapyrilene causes acute periportal hepatotoxicity in rats are not yet elucidated. This study investigated the effects of modulators of cytochrome P450 (CYP) activity on the hepatotoxicity of methapyrilene and also the effect of methapyrilene on hepatic CYP. Pretreatment of male Han Wistar rats with p-naphthoflavone, phenobarbitone, butylated hydroxytoluene, piperonyl butoxide, Aroclor 1254, or cobalt protoporphyrin IX, agents known to modify hepatic CYP, all afforded some degree of protection against a hepatotoxic dose of methapyrilene (150 mg/kg x 3 days p.o.), as assessed by clinical chemistry and histology. Total hepatic CYP depletion by cobalt protoporphyrin IX treatment indicated CYPmediated bioactivation was a prerequisite for methapyrilene-induced hepatotoxicity. Protection against hepatic damage was strongly associated with /3-naphthoflavone induction of CYP1A and phenobarbitone-associated CYP2B induction. However, the role of CYP3A, which is constitutively expressed in the liver and induced by piperonyl butoxide, butylated hydroxytoluene, or Aroclor 1254, was unclear. Modulation of FAD monooxgenase activity by methimazole pretreatment was not associated with increased methapyrilene-induced hepatotoxicity. Methapyrilene treatment alone specifically decreased microsomal enzyme activity markers for CYP2C11, CYP3A, and CYP2A and pretreatment with all the hepatic enzyme-inducing agents specifically prevented the loss of CYP2C11. Together this suggested that CYP2C11 was responsible for the suicide substrate bioactivation of methapyrilene and the toxicologic outcome largely relied upon an abundance of detoxifying enzymes present in the liver, o Methapyrilene is an ethylenediamine H, histamine receptor antagonist which has been used for over 20 years, principally as a sleep aid and in cold and allergy formulations. Subsequently, methapyrilene was withdrawn from clinical use when it was found to be hepatocarcinogenic, following chronic administration in rats (Lijinsky et ai, 1980), although not in 'To whom correspondence should be addressed. Fax: 0171 982 6135. E-mail: c.j.powell@mds.qmw.ac.uk. mice, guinea pigs, or hamsters (Brennan and Creasia, 1982; Lijinsky et ai, 1983). In the rat, acute administration of methapyrilene has been found to damage the periportal region of the liver (Graichen et ai, 1985); however, the underlying biochemical mechanisms responsible are poorly understood.Methapyrilene undergoes extensive metabolism in vivo, in cultured hepatocytes and in microsomes Schmitz, 1986, 1987; Singer et ai, 1987;Kelly et al., 1992). While many metabolites of methapyrilene have been identified, the metabolite(s) responsible for hepatic damage in rats remains elusive. Species differences in the metabolism of methapyrilene seem largely quantitative rather than qualitative (Kammerer and Schmitz, 1987;Lampe and Kammerer, 1990). It is plausible, therefore, that the species differences in methapyrilene-induced hepatotoxicity may be explained by differences in ...

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Species differences in the metabolism and macromolecular binding of methapyrilene: a comparison of rat, mouse and hamster

Cited by 12 publications

References 28 publications

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

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

Identification of the Thiophene Ring of Methapyrilene as a Novel Bioactivation-Dependent Hepatic Toxicophore

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

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