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At least 19 recordsLinked to original sources
PubMed1993

The evaluation of methapyrilene for bacterial mutation with metabolic activation by Aroclor-induced, methapyrilene-induced and noninduced rat-liver S9.

The antihistamine methapyrilene (MP) has been shown to be a potent hepatocarcinogen in rats. However, it has demonstrated little genotoxic activity in a wide variety of short-term tests. In this study, Fischer 344 rats were fed a carcinogenic dose of 0.1% methapyrilene in the diet for 10 weeks prior to sacrifice. S9 was prepared from the livers of the control, MP-treated and Aroclor-induced Fischer 344 rats. Each type of S9 was analyzed for mixed function oxidase activity, cytochrome P-450, and protein content. MP was then evaluated for mutagenicity in 6 strains of S. typhimurium (TA1535, TA1537, TA98, TA100, TA2638 and TA104) and one strain of E. coli (WP2uvrA-) using the standard plate-incorporation assay. MP was not mutagenic in any of the 7 bacterial strains when tested at concentrations < or = 10 mg/ml in the presence of each type of S9. However, in the absence of metabolic activation, an approximate 2-fold increase in revertants was noted with strain TA1535. The data from this study show that MP was not converted to a mutagenic metabolite by any of the three S9 types examined. However, the "weak" positive response with strain 1535 in the absence of metabolic activation indicates that further research is needed to elucidate the mechanism of action of this rat carcinogen.

Animals↗
PubMed1987

The effect of chronic methapyrilene treatment on methapyrilene metabolism in vitro.

Rats were fed 100 or 1000 p.p.m. methapyrilene (MPH) in their diet for 1, 2, 4, 8 or 16 weeks. Liver microsomes were prepared from both control and treated rats. After incubation with 1 mM MPH, eight metabolites were detected and six were quantitated. Five of the metabolites have been previously identified as 2-hydroxymethyl-thiophene (ThM), thiophene-2-carboxylic acid (ThCA), N-(2-thienylmethyl)-2-aminopyridine (TMAP), N-2-pyridyl-N',N'-dimethylethylenediamine (PMED), and 2-aminopyridine (AP). Three other metabolites have been tentatively identified based on their mass spectral fragmentation patterns as normethapyrilene (N-MPH), (5-hydroxypyridyl)methapyrilene (HP-MPH), and methapyrileneamide (MPH-A). The same metabolites were found in both control and treated animals, the most abundant being N-MPH and PMED. Pretreatment with MPH resulted in inhibition of both consumption of MPH and formation of some metabolites. However increases in the formation of all of the metabolites also occurred under different treatment conditions. In both control and treated tissue, the preliminary mass balance was less than 55%, except in incubations with tissue from rats treated with 1000 p.p.m. for 8 or 16 weeks where it was 92 and 89%, respectively. Dramatic increases in the fraction of TMAP, MPH-A, N-MPH, and HP-MPH relative to MPH consumed account for the increase in the mass balance after 8 weeks pretreatment with 1000 p.p.m. MPH, and increases in the amounts of PMED, HP-MPH and ThCA account for the higher mass balance after 16 weeks. The toxicological consequences of these complex metabolic changes may be important in the induction of cancer by MPH.

Aminopyridines↗
PubMed1992

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

Methapyrilene (MP) is a rat-specific liver carcinogen that alters mitochondrial number and morphology both in vivo and in vitro. This biological phenomenon may be due to the effects of MP on mitochondrial function. To test this hypothesis, studies were conducted to examine the effects of MP on DNA and protein synthesis and respiration in isolated mitochondria. DNA and protein synthesis activities were measured using [3H]thymidine and [3H]leucine incorporation. Mouse liver mitochondria were also examined for comparison since no tumor formation or alterations in mitochondrial morphology have been associated with MP treatment in mice. A significant decrease in basal DNA and protein synthesis levels was observed in mitochondria isolated from rats and mice following in vivo MP treatment. This effect could not be reproduced when mitochondria were exposed to 0 or 100 microM MP following isolation, despite the presence of an S9 activation system. Electron microscopic examinations were performed on isolated rat mitochondria and revealed morphologic differences between mitochondria from naive and MP-treated rats. Although significant differences in State 3 and State 4 respiratory rates were noted, the respiratory control ratio, ADP/O ratio, and uncoupler-stimulated respiratory rates were unaffected. Results demonstrate that: (1) MP irreversibly depresses DNA and protein synthesis in a majority of mitochondria, despite only localized morphologic changes; (2) these changes are not reflected by a decrease in respiratory function; and (3) depression of DNA and protein synthesis does not correlate with carcinogenic susceptibility.

Animals↗
PubMed1987

Methapyrilene is a genotoxic carcinogen: studies on methapyrilene and pyrilamine in the L5178Y/TK +/- mouse lymphoma assay.

Methapyrilene (MP), a sedating antihistamine, is a potent rat hepatocarcinogen which has been thought to be non-genotoxic on the basis of the negative results in a small number of short-term mutagenicity tests. The present studies show that MP is a moderately active mutagen in the L5178Y/TK +/-----TK-/- mouse lymphoma assay (MLA) in the presence of aroclor-induced rat-liver S9, and that it induces predominantly small-colony thymidine kinase-deficient (TK-/-) mutants of demonstrated chromosomal origin. 10 of 12 small colony TK-/- mutants analyzed by banded karyotype (230-band level of resolution) show aberrations to chromosome 11b, the known location of the single functional TK gene in these cells. The observed aberrations from nine of the mutants included insertions, deletions and translocations while the tenth mutant had highly rearranged, multiple copies of chromosome 11 segments. By varying the concentrations of the S9 protein and cofactors it was shown that our standard S9 composition was close to optimum for activating MP to a mutagen. The activity and stability of various lots of S9 prepared in-house or purchased from a contract laboratory revealed significant differences. The ability of 2 lots of in-house S9 to activate a standard concentration of MP increased rapidly over the first 4 weeks of liquid nitrogen storage then declined slowly over the next 16 weeks. Three separate lots of purchased S9 were essentially inactive for the first 2 weeks of liquid nitrogen storage then increased in activity thereafter; these were the only occasions in which MP was not mutagenic in our hands. The mutagenic activity of pyrilamine (PYR), a structurally related antihistamine which is far less carcinogenic in rats, but easily detected in short-term tests as being genotoxic, was also investigated in the MLA. PYR was slightly less mutagenic than MP over a comparable range of concentrations, and also induced predominantly small-colony mutants. These studies fail to adequately explain the great carcinogenic differences between these two compounds, but are consistent with the potent hepatocarcinogenicity of MP resulting through a mutagenic mechanism.

Aminopyridines↗
PubMed2000

NTP Hepatotoxicity Studies of the Liver Carcinogen Methapyrilene Hydrochloride (CAS No. 135-23-9) Administered in Feed to Male F344/N Rats.

Methapyrilene hydrochloride is a histamine H(1)-receptor antagonist that was an active ingredient in many over-the-counter cold and allergy medications. In the mid- to late 1970s, studies in rats suggested that methapyrilene hydrochloride was a hepatocarcinogen, and the drug was removed from these preparations. In most cases, methapyrilene hydrochloride was replaced by pyrilamine maleate, a structurally similar analogue. As part of a program to investigate mechanisms of toxicity whereby structurally similar chemicals produce different toxicities, these chemicals were studied for induction of cell proliferation and protein alterations by two-dimensional gel electrophoresis in the liver of F344/N rats. A complete toxicologic evaluation was not needed for this research-oriented study. Rather, the goal of the present study was to provide retrospective data from subchronic toxicity studies with the known rat carcinogen methapyriline hydrochloride that could then be used to predict the potential carcinogenicity of unknown chemical agents and that could also be compared with similar data on the structural analogue pyrilamine maleate. Pyrilamine maleate differs from methapyrilene hydrochloride in the substitution of the thienyl ring with a paramethoxyphenyl ring. Pyrilamine maleate has been shown to produce an equivocal increase in the incidences of liver neoplasms in rats in 2-year feed studies, but only at 2,000 ppm, indicating that its potency, if any, to produce neoplasms is much less than that of methapyriline hydrochloride. The hepatocarcinogenic peroxisome proliferator Wy-14,643 was included in this study as a positive control that is known to induce cell proliferation, as well as protein alterations, in the liver. In the 14-week study of methapyrilene hydrochloride, groups of 40 male F344/N rats were given 0, 50, 100, 250, or 1,000 ppm methapyrilene hydrochloride, 1,000 ppm pyrilamine maleate (negative control), or 50 ppm Wy-14,643 ( positive control) in feed. Rats in all groups were administered bromodeoxyuridine (BrdU) by osmotic minipump for the assessment of hepatocyte proliferation. Ten rats from each group were evaluated on days 15, 29, and 43 and at 14 weeks. At these times, samples of liver tissue were analyzed for evidence of cell proliferation via BrdU labeling and proliferating cell nuclear antigen (PCNA) labeling. There were no exposure-related deaths. Low mean body weights were generally observed in the 1,000 ppm methapyriline hydrochloride group and in the positive control group. Final mean body weights and mean body weight gains of rats exposed to 1,000 ppm methapyrilene hydrochloride were significantly less than those of the untreated control group at all time points. The final mean body weights of rats in the positive control group were significantly less than those of the untreated control group for rats evaluated on days 29 and 43 and at week 14; the mean body weight gains of rats in the positive control group were significantly less than those of the untreated control group on day 29 and at week 14. Feed consumption by rats exposed to 1,000 ppm methapyrilene hydrochloride was significantly less than that by the untreated control group throughout the study. The predominant clinical observation related to methapyrilene hydrochloride exposure was thinness in rats exposed to 1,000 ppm; this finding was first observed on day 29. On days 29 and 43 and at 14 weeks, the absolute liver weights of rats exposed to 1,000 ppm methapyrilene hydrochloride were significantly less than those of the untreated control group. At all time points, the relative liver weights of rats exposed to 1,000 ppm methapyrilene hydrochloride and the absolute and relative liver weights of positive control rats were significantly greater than those of the untreated control group. No significant differences in liver weights were observed between the negative and untreated control groups at any time point. Hepatic lesions were observed predominantly in the 250 and 1,000 ppm methapyrilene hydrochloride groups and in the positive control group. The incidences of bile duct hyperplasia, hepatocyte necrosis, hepatocyte mitosis, and hepatocyte hypertrophy in rats in the 1,000 ppm group were significantly greater than those in the untreated control group at all time points. The severities of hepatocyte hypertrophy and hepatocyte mitosis in 1,000 ppm rats were generally mild to moderate; the lesions occurring in 250 ppm animals were less severe. At each time point, the incidence of bile duct hyperplasia in 250 ppm rats was significantly greater than that in the untreated control group. The incidences of hepatocyte mitosis on days 15 and 29 and the incidences of hepatocyte necrosis on days 29 and 43 in rats in the 250 ppm group were significantly greater than those in the untreated control group. Incidences of pigmentation in the 250 and 1,000 ppm methapyrilene hydrochloride groups were significantly greater than those in the untreated control group on days 29 and 43 and at 14 weeks. In the positive control group, the incidences of granulomatous inflammation were significantly greater than those in the untreated control group on days 15, 29, and 43. The incidences of hepatocyte hypertrophy and hepatocyte mitosis in the positive control group were significantly greater than those in the untreated control group on days 15, 29, and 43. The incidence of hepatocyte hypertrophy was also significantly increased in the positive control group at 14 weeks. The severity of hepatocyte hypertrophy in the 1,000 ppm methapyrilene hydrochloride group was generally greater than that in the positive control group at each time point. In general, methapyriline hydrochloride produced a dramatic and sustained increase in hepatic cell proliferation over 14 weeks, whereas pyrilamine maleate at the same concentration produced few if any effects. Wy-14,643 also induced a large increase in cell proliferation which declined over time, as has been observed in previous studies. The mean BrdU labeling indexes of the 250 and 1,000 ppm methapyrilene hydrochloride groups were generally significantly greater than those of the untreated controls at all time points. In the negative control group, the BrdU labeling index was significantly less than that of the untreated control group on day 29. The BrdU labeling index in the positive control group was significantly greater than that of the untreated control group at all time points. On day 43 and at week 14, the mean PCNA labeling indexes of the 1,000 ppm methapyrilene hydrochloride group were significantly greater than those of the untreated control group. The mean PCNA labeling indexes of the negative control group were significantly less than those of the untreated control group on days 29 and 43. On day 29, the mean PCNA labeling index of the positive control group was significantly greater than that of the untreated control group. The mitotic indexes of the 1,000 ppm methapyrilene hydrochloride group were significantly greater than those of the untreated control group at all time points. The mitotic indexes of the 250 ppm group were significantly greater than those of the untreated control group on day 43 and at week 14. At least 32 proteins underwent significant abundance changes at the highest exposure concentration of methapyrilene hydrochloride, and 39 protein changes were observed in the positive control group. Many, but not all, of the protein changes in the methapyrilene hydrochloride-exposed animals also occurred in the positive control group. Treatment with pyrilamine maleate produced no significant quantitative protein changes, as judged by the same criteria used for methapyrilene hydrochloride and Wy-14,643. Methapyrilene hydrochloride produced covalent modification of mitochondrial proteins as measured by the charge modification index. PCNA abundance in liver samples from the 250 and 1,000 ppm methapyrilene hydrochloride exposure groups on day 43 was significantly greater than that of the untreated control group. Results of tests for induction of mutagenicity by methapyrilene hydrochloride were negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and in L5178Y mouse lymphoma cells, with and without S9 metabolic activation. However, positive responses were obtained in cytogenetic tests with cultured Chinese hamster ovary cells, in which methapyrilene hydrochloride induced sister chromatid exchanges and chromosomal aberrations. The increases in sister chromosome exchanges were obtained with and without S9, but chromosomal aberrations were increased only in the presence of S9. In summary, the significance of the increased hepatic cell proliferation and the protein alterations observed in this study is not definite, but may be of predictive value for assessing the toxicity and carcinogenicity of chemicals in preclinical assays. A chemical which does not produce an increase in cell proliferation or a large number of protein changes may be considered safer than a similar chemical that produces many such changes.

Journal Article↗
PubMed1998

Methapyrilene hepatotoxicity is associated with oxidative stress, mitochondrial disfunction and is prevented by the Ca2+ channel blocker verapamil.

Methapyrilene (MP) is an unusual hepatotoxin in that it causes periportal necrosis in rats. The mechanism of acute methapyrilene hepatotoxicity has, therefore, been investigated in cultured male rat hepatocytes. Addition of methapyrilene to rat hepatocytes resulted in a time- and dose-dependent loss in cell viability between 4 and 8 h of incubation as judged by cellular enzyme leakage. The cytochrome P450 (CYP) inhibitor metyrapone protected against methapyrilene-mediated toxicity suggesting that MP is metabolised by CYP for toxicity. The concentration-dependent protection from methapyrilene toxicity afforded by metyrapone correlated with an inhibition of microsomal CYP2C11-associated androstenedione 16alpha hydroxylase activity, and hepatocytes prepared from hypophysectomised rats (containing reduced levels of microsomal immunodetectable CYP2C11 and associated androstenedione 16alpha hydroxylase activity) showed resistance to the toxic effects of methapyrilene. These data suggest that the toxicity of methapyrilene is predominantly dependent on the CYP2C11 isoform. Treatment of hepatocytes with a toxic concentration of MP caused oxidative stress as indicated by increases in NADP+ levels within 2 h and cellular thiol oxidation as evidenced by a reduction--but not complete loss--in glutathione levels. Methapyrilene hepatotoxicity was associated with an early loss in mitochondrial function, as indicated by mitochondrial swelling and significant losses in cellular ATP within 2 h. Co-incubation of methapyrilene-treated hepatocytes with inhibitors of inner mitochondrial transition permeability pore opening--cyclosporin A or the thiol reductant dithiothreitol--abrogated cell death suggesting that pore opening and loss of mitochondrial Ca2+ homeostasis play a significant role in methapyrilene-mediated cell death. Co-incubation of methapyrilene-treated hepatocytes with the phenylalkylamine calcium channel blocker verapamil--but not by treating cells in a nominally calcium-free medium--also abrogated cell death, suggesting that if Ca2+ is involved in cell killing then it is dependent on an intracellular Ca2+ pool. Pre-treatment of hepatocytes for 1 h with verapamil--to inhibit intracellular Ca2+ pool filling--increased the potency of verapamil protection against methapyrilene toxicity by approximately 100-fold. Taken together, these data indicate that methapyrilene intoxication leads to mitochondrial disfunction and suggest a critical role for a loss of mitochondrial Ca2+ homeostasis in this model of hepatocyte death.

Adenosine Triphosphate↗
PubMed2000

Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation.

The mechanisms by which acute administration of methapyrilene, an H(1)-receptor antihistamine causes periportal necrosis to rats are unknown. This study investigated the role of the hepato-biliary system in methapyrilene hepatotoxicity following daily administration of 150 mg/kg per day over 3 consecutive days. Biliary metabolites of methapyrilene were tentatively identified. In male Han Wistar rats administration of methapyrilene significantly increased hepatic reduced glutathione (GSH) to 140% of control levels 24 h following the last dose. There were no significant changes in the activities of glutathione-related enzymes, glutathione peroxidase (GPx) and reductase (GSH), glutathione S-transferase (GST), and gamma-glutamyl cysteine synthetase (gamma-GCS) over 3 days of methapyrilene administration. Methapyrilene treatment resulted in no significant increase in excretion of biliary oxidized glutathione (GSSG), a sensitive marker of oxidative stress in vivo, following the third dose. [3H]Methapyrilene-derived radioactivity was detected in bile, to a greater extent than in feces, indicating that methapyrilene and/or metabolites underwent enterohepatic recirculation. Cannulation and exteriorization of the bile duct (to interrupt enterohepatic recirculation) afforded some protection against the hepatotoxicity, assessed by clinical chemistry and histopathology. Liquid chromatography-mass spectrometry (LC-MS) analysis of bile indicated the presence of unmetabolized methapyrilene, methapyrilene O-glucuronide and desmethyl methapyrilene O-glucuronide. These data demonstrate that acute methapyrilene hepatotoxicity in vivo is not a consequence of GSH depletion, or oxidative stress, but that enterohepatic recirculation of biliary metabolites may be important. Progressive exposure to non-oxidizing, reactive metabolic intermediates may be responsible for hepatotoxicity.

Alanine Transaminase↗
PubMedDate not supplied

Plasma elimination and urinary excretion of methapyrilene in the rat.

The metabolism and elimination of methapyrilene (2-[(2-dimethylaminoethyl)-2-thenylamino]pyridine) were characterized after the iv administration of 0.7 mg/kg or 3.5 mg/kg methapyrilene HCl plus [14C]methapyrilene HCl to adult male Fischer-344 rats. Approximately 40% and 35% of the administered dose was excreted in the urine in the first 24 hr in the low and high dose groups, respectively, as determined by liquid scintillation spectrophotometry. Fecal excretion accounted for 38% and 44% of the administered dose in the first 24 hr in the low and high dose groups, respectively, as confirmed via combustion analysis. The 24-hr urinary metabolic products consisted of one major and five minor radiolabeled compounds. The major metabolite was isolated with reversed-phase HPLC and identified as methapyrilene N-oxide. This was accomplished by comparison of the chromatographic and mass spectral characteristics of this metabolite with that of authentic methapyrilene N-oxide. Methapyrilene and mono-N-desmethyl methapyrilene also were identified after isolation with reversed-phase HPLC and comparison of their mass spectral and/or chromatographic properties with those of authentic compounds. The plasma metabolic profile was essentially the same as the urinary profile. The elimination of methapyrilene from plasma occurred through a first-order process. The terminal plasma elimination t1/2 of methapyrilene did not increase with increasing doses (2.75 hr, 0.7 mg/kg; 2.81 hr, 3.5 mg/kg); thus, methapyrilene does not exhibit dose-dependent elimination over this 5-fold dose range.

Animals↗
PubMed1998

Effects of induction and inhibition of cytochromes P450 on the hepatotoxicity of methapyrilene.

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 beta-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 CYP-mediated bioactivation was a prerequisite for methapyrilene-induced hepatotoxicity. Protection against hepatic damage was strongly associated with beta-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.

Animals↗
PubMed1982

Inability of methapyrilene to induce sister chromatid exchanges in vitro and in vivo.

The induction of sister chromatid exchanges (SCE) by the hepatocarcinogen methapyrilene hydrochloride was investigated using appropriate in vitro and in vivo mammalian cell systems. Methapyrilene, even at the maximum tolerated dose, did not induce SCE in Chinese hamster ovary cells (CHO) or when CHO cells or hamster lung fibroblasts, V-79, were cocultivated with early cultures of rat liver epithelial cells, which are known to metabolize different classes of chemical carcinogens to active forms. Moreover, a hybrid clone of cells (formed by fusion of CHO cells with rat liver epithelial cells), which is highly sensitive to SCE formation by a number of xenobiotics, failed to produce SCE after treatment with methapyrilene. Experiments in vivo with bone marrow cells and in vitro with CHO cells cocultivated with primary hepatocytes from rats also confirmed the inability of methapyrilene to induce SCE in the indicator cells. Since aflatoxin B1 induced SCE in the in vitro and in vivo models, it may be concluded that methapyrilene does not induce SCE at a concentration which is not cytotoxic to the indicator cells in the different systems described. Autoradiographic studies in cultured rat liver cells with tritiated methapyrilene showed that the label was localized in the cytoplasm but not in the interphase nuclei or in the metaphase chromosomes, indicating a lack of interaction of methapyrilene with the nuclear macromolecules of the putative target cells for methapyrilene.

Aminopyridines↗
PubMed1977

Methapyrilene toxicity.

Seven cases of drug overdosage involving methapyrilene have been presented, five of which resulted in death. Methapyrilene blood levels ranged fron 1.2 to 3.0 mg% (Table 2). Five of the seven cases involved multiple drug dosage with ethanol, salicylamide, amobarbital, secobarbital, and/or scopolamine. Of the remaining cases, involving only methapyrilene, ome fatality occurred at a blood level of 2.7 mg%. The surviving case involved the reported ingestion of 100 tablets of Sleep-eze (2.5 gm methapyrilene), wherein serial lavage removed 1.1 gm of methapyrilene. Urinalysis revealed 2.52 mg% of methapyrilene in 1300 ml of urine. The methapyrilene blood level was too low to quantitate.

Adult↗
PubMed1982

Methapyrilene effects on initiation and promotion of gamma-glutamyl-transpeptidase positive foci in rat liver.

The initiating and promoting effects of methapyrilene were evaluated using the hepatic enzyme-altered foci bioassay. Male Sprague-Dawley rats were partially hepatectomized and 24 hours later were administered either methapyrilene or nitrosodiethylamine by oral gavage. Subsequently, the animals were promoted with 500 ppm2 phenobarbital or 200 ppm methapyrilene in drinking water for eight weeks. Fresh frozen sections of liver were then stained and scored for gamma-glutamyl-transpeptidase (GGT)-positive foci. Methapyrilene, when tested as the nominal initiator at a single dose of 50 mg/kg or at two doses of 130 mg/kg and promoted by phenobarbital, did not induce foci above background levels. However, when substituted for phenobarbital as the promoting agent following nitrosodiethylamine initiation, methapyrilene enhanced enzyme-altered foci formation to an equal or greater extent than did the promoter phenobarbital. These results suggest that the carcinogenic effects of methapyrilene may be related to its ability to enhance hepatic tumorigenesis.

Aminopyridines↗
PubMed1986

Carcinogenicity studies of some analogs of the carcinogen methapyrilene in F344 rats.

Four antihistaminic drugs similar in structure to the rat liver carcinogen methapyrilene were administered to comparable groups of male and female F344 rats in their drinking water for most of their lifetime (80-108 weeks). The concentrations were 0.1% or 0.05% and the total doses received by the animals were comparable with that of methapyrilene which induced 100% incidence of liver neoplasms. No increase in incidence of liver neoplasms was observed after treatment with any of the four compounds, thenyldiamine, chlorothen, methafurylene, or methaphenilene, although each differed structurally from methapyrilene only in one atom or one position of substitution. There were a few animals with neoplasms not usually found in untreated F344 rats, but none of these was found in statistically significant numbers. These results suggest that none of the four analogs of methapyrilene was carcinogenic under the conditions of this study, and that the property of inducing liver neoplasms in rats was confined to the intact methapyrilene molecule.

Aminopyridines↗
PubMed1984

A study of the potential genotoxicity of methapyrilene and related antihistamines using the hepatocyte/DNA repair assay.

Methapyrilene and four related antihistamines were evaluated for their ability to cause DNA repair measured autoradiographically as unscheduled DNA synthesis (UDS) in primary cultures of Fischer-344 rat hepatocytes. Methapyrilene failed to induce UDS at all doses tested while pyrilamine and tripelennamine induced a concentration-dependent increase in DNA repair. Doxylamine and thenyldiamine, previously untested in this system, induced a weak response at the highest non-toxic doses tested. Methapyrilene was clearly cytotoxic at doses of 100 microM and higher, as judged by morphology, and precursor incorporation into RNA and protein. Precursor incorporation into RNA was irreversibly inhibited 90% and 55% at 1000 microM and 100 microM methapyrilene, respectively, while precursor incorporation into protein was inhibited 80% and 60%. These data verify the genotoxicity of pyrilamine and tripelennamine and the failure of methapyrilene to elicit DNA repair, and suggest that doxylamine and thenyldiamine may be weak DNA-damaging agents.

Aminopyridines↗
PubMed1985

Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology.

Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens.

Alanine Transaminase↗
PubMed1981

Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of methapyrilene.

The popular antihistamine methapyrilene [N,N-dimethyl-N'-(2-pyridyl)-N'-(2-thienylmethyl)-1,2-ethanediamine] recently has been shown to be a potent hepatocarcinogen. Metabolic studies with rabbit liver 100000g microsomal preparations have resulted in the partial characterization of the in vitro metabolic profile of methapyrilene. Evidence for the formation of the N-oxide and the three possible carbinolamines resulting from the NADPH-dependent oxidation of the (dimethylamino)ethyl side chain nitrogen and carbon atoms of methapyrilene is presented. Attempts to trap iminium ion intermediates with electrophilic alkylating potential by coincubating methapyrilene with sodium cyanide have led to the isolation of N-(cyanomethyl)normethapyrilene. The possibility of characterizing the iminium ion intermediate that would result from the oxidative deamination of the dimethylamino moiety was precluded by the chemical instability of the corresponding alpha-cyano amine, which undergoes a spontaneous retro-Michael reaction and hydrolysis to the corresponding amide. The results are discussed in terms of the metabolic activation of methapyrilene to potential alkylating species.

Aminopyridines↗
PubMed1989

S-adenosylmethionine, S-adenosylhomocysteine and DNA methylation levels in the liver of rats fed methapyrilene and analogs.

The antihistamine methapyrilene (hydrochloride) and four close structural analogs, methaphenilene, methafurylene, thenyldiamine and clorothen, were given to rats at a concentration of 0.1% in drinking water for 34 weeks. Only methapyrilene produced notable histopathological changes in the liver, bile duct hyperplasia and focal cellular change. Methapyrilene produced an early and persistent elevation in the ratio of S-adenosylmethionine to S-adenosylhomocysteine, which was 2.8 times the control levels at 34 weeks; none of the other antihistamines produced so high a ratio or altered the ratio as early. Methapyrilene, but not the other antihistamines, produced a significant increase in the methylation of liver DNA at 20 and 34 weeks, as measured by the level of 5-methyldeoxycytidine. The increase in deoxycytosine methylation is so far the only detected effect of the carcinogen methapyrilene on DNA which is absent in rats treated with its non-carcinogenic analogs.

Aminopyridines↗