Methapyrilene (hydrochloride)
(Synonyms: 盐酸美沙吡林,Thenylpyramine hydrochloride) 目录号 : GC48805
An H1 receptor antagonist and non-genotoxic carcinogen
Cas No.:135-23-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Methapyrilene is a histamine H1 receptor antagonist (Ki = 4.5 nM) and non-genotoxic carcinogen.1,2 Dietary administration of methapyrilene (0.1%) induces liver tumors in rats, with greater than 50% of rats incurring distant metastases.3 It decreases the acetylation of histone 3 lysine 9 (H3K9) and H3K56, as well as the di- and trimethylation of H3K4 and H4K20, respectively, in rat liver when administered at 40 mg/kg per day for six weeks.2 Methapyrilene also increases 4-hydroxy nonenal (4-NHE) protein adducts in rat liver. Formulations containing methapyrilene were previously used as sleep aids.
1.Tran, V.T., Chang, R.S.L., and Snyder, S.H.Histamine H1 receptors identified in mammalian brain membranes with [3H]mepyramineProc. Natl. Acad. Sci. U.S.A.75(12)6290-6294(1978) 2.Shpyleva, S., Dreval, K., de Conti, A., et al.Editor's highlight: Organ-specific epigenetic changes induced by the nongenotoxic liver carcinogen methapyrilene in fischer 344 ratsToxicol. Sci.156(1)190-198(2017) 3.Lijinsky, W., Reuber, M.D., and Blackwell, B.N.Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochlorideScience209(4458)817-819(1980)
| Cas No. | 135-23-9 | SDF | |
| 别名 | 盐酸美沙吡林,Thenylpyramine hydrochloride | ||
| Canonical SMILES | CN(C)CCN(CC1=CC=CS1)C2=NC=CC=C2.Cl | ||
| 分子式 | C14H19N3S•HCl | 分子量 | 297.8 |
| 溶解度 | DMF: 15 mg/ml,DMSO: 10 mg/ml,Ethanol: 1 mg/ml,PBS (pH 7.2): 1 mg/ml | 储存条件 | -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.358 mL | 16.7898 mL | 33.5796 mL |
| 5 mM | 0.6716 mL | 3.358 mL | 6.7159 mL |
| 10 mM | 0.3358 mL | 1.679 mL | 3.358 mL |
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Effect of Methapyrilene hydrochloride on hepatic intracellular iron metabolism in vivo and in vitro
Toxicol Lett 2017 Nov 5;281:65-73.PMID:28935588DOI:10.1016/j.toxlet.2017.09.011.
The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen Methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with Methapyrilene at doses 40 and 80mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene. A decrease in the level of TF and an increase in the level of FTL also occurred in methapyrilene-treated differentiated HepaRG cells, indicating the existence of interspecies and in vitro-in vivo similarities in the disturbance of cellular iron homeostasis upon liver injury. In contrast, there was minimal overlap in the expression of liver toxicity-marker genes in the livers of rats and in HepaRG cells treated with Methapyrilene. Importantly, the decrease of transferrin at mRNA and protein levels occurred after the treatment with a low dose of Methapyrilene that exhibited minimal cytotoxicity. These results demonstrate the significance of the dysregulation of hepatic iron metabolism in the pathogenesis and mechanism of chemical-induced liver toxicity and suggest that these changes may be sensitive and useful indicators of potentially hepatotoxic chemicals.
NTP Hepatotoxicity Studies of the Liver Carcinogen Methapyrilene hydrochloride (CAS No. 135-23-9) Administered in Feed to Male F344/N Rats
Toxic Rep Ser 2000 Feb;46:1-C7.PMID:11986676doi
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.
Trace analysis of the antihistamines Methapyrilene hydrochloride, pyrilamine maleate and triprolidine hydrochloride monohydrate in animal feed, human urine and wastewater by high-performance liquid chromatography and gas chromatography with nitrogen-phosphorus detection
J Chromatogr 1984 Jan 20;283:251-64.PMID:6142898DOI:10.1016/s0021-9673(00)96260-5.
Toxicological evaluation of the antihistamines Methapyrilene hydrochloride, pyrilamine maleate, and triprolidine hydrochloride monohydrate using Methapyrilene hydrochloride as the positive indicator was investigated as part of a structure-activity relationship study in rats and mice. Prerequisites for the toxicological tests were the development of analytical procedures to certify the dose, homogeneity and stability of the drugs in animal feed and to monitor human urine for possible exposure and to ensure removal of the test agents from wastewater prior to its discharge into the environment. A high-performance liquid chromatographic (HPLC) system was developed using a fluorescence detector for the determination of Methapyrilene hydrochloride and pyrilamine maleate in feed at levels as low as 100 ng/g and in human urine as low as 1 ng/g. An HPLC-UV procedure was developed for the determination of triprolidine hydrochloride monohydrate in feed at levels as low as 10 micrograms/g. Data concerning p-values, extraction efficiencies from feed and stability experiments in feed are presented for these antihistamines. A gas chromatographic procedure using a nitrogen-phosphorus detector was also developed for determining the three antihistamines in admixture in wastewater at levels as low as 10 ng/g.
The 14-day repeated dose liver micronucleus test with Methapyrilene hydrochloride using young adult rats
Mutat Res Genet Toxicol Environ Mutagen 2015 Mar;780-781:123-7.PMID:24768639DOI:10.1016/j.mrgentox.2014.04.004.
The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.
DNA damage induced by the antihistaminic drug Methapyrilene hydrochloride
Mutat Res 1982 Mar;103(3-6):213-8.PMID:6123945DOI:10.1016/0165-7992(82)90045-8.
Treatment of primary cultures of rat hepatocytes with the antihistaminic drug, Methapyrilene hydrochloride, stimulated DNA-repair synthesis up to 7-fold and caused the formation of alkaline-labile lesions in hepatocellular DNA. These data clearly demonstrate that Methapyrilene hydrochloride is a DNA damaging agent. In view of a recent report and our own findings we suggest that this antihistamine has the properties of a complete carcinogen.