Disease relevance of Thenylpyramine

• The findings suggest that multiple pathways may be followed in the development of methapyrilene-induced liver cancer that are similar to those found in rats exposed to many other hepatic carcinogens [1].
• Although methapyrilene (MP) produces hepatocellular carcinomas in rats, it does not elicit many of the cellular responses induced by other hepatocarcinogens [2].
• Examination of genotoxicity, toxicity and morphologic alterations in hepatocytes following in vivo or in vitro exposure to methapyrilene [3].
• Only methapyrilene produced notable histopathological changes in the liver, bile duct hyperplasia and focal cellular change [4].
• Weak and unexpected mutagenicity to Salmonella of the rat hepatocarcinogen methapyrilene [5].

High impact information on Thenylpyramine

• Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride [6].
• Carcinogenesis by nonmutagenic chemicals: early response of rat liver cells induced by methapyrilene [2].
• 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 [7].
• Inability of methapyrilene to induce sister chromatid exchanges in vitro and in vivo [7].
• 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 [7].

Chemical compound and disease context of Thenylpyramine

• Mutation spectrum of a binary mixture of mutagens (methapyrilene and sodium azide) in strain TA1535 of Salmonella [8].
• Methapyrilene, four structurally related antihistamines, three metabolites of methapyrilene and two products of the reaction of methapyrilene with nitrite were all tested for mutagenicity to Salmonella typhimurium [9].

Biological context of Thenylpyramine

• 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 [7].
• Methapyrilene kinetics and dynamics [10].
• Methapyrilene induces membrane lipid peroxidation of rat liver cells [11].
• The results are discussed in terms of the metabolic activation of methapyrilene to potential alkylating species [12].
• S-adenosylmethionine, S-adenosylhomocysteine and DNA methylation levels in the liver of rats fed methapyrilene and analogs [4].

Anatomical context of Thenylpyramine

• A study was undertaken to characterize the H1 receptor blockade, central nervous system depressant properties, and kinetic parameters of methapyrilene in man [10].
• Feeding methapyrilene for 1, 2 and 3 days resulted in lipid peroxidation of both mitochondrial and microsomal membranes [11].
• The extent of interaction of radioactive methapyrilene with liver nucleic acids was exceedingly small and did not differ significantly from the binding to nucleic acids in kidney, lung, or pancreas, which are not target organs of this carcinogen in rats [13].
• Two weeks of treatment with the liver carcinogen methapyrilene induced a significant increase in mitochondria of periportal hepatocytes in F344 rats [14].
• [3H]Methapyrilene-derived radioactivity was detected in bile, to a greater extent than in feces, indicating that methapyrilene and/or metabolites underwent enterohepatic recirculation [15].

Associations of Thenylpyramine with other chemical compounds

• The hepatocarcinogen methapyrilene but not the analog pyrilamine induces sustained hepatocellular replication and protein alterations in F344 rats in a 13-week feed study [16].
• The reactions of sodium nitrite and methapyrilene were studied in aqueous solution at neutral pH and under simulated gastric fluid conditions [17].
• Fast-atom bombardment and thermospray mass spectrometry for the characterization of two glucuronide metabolites of methapyrilene [18].
• Two up-regulated proteins, glutathione S-transferase with methapyrilene and peroxisomal bifunctional enzyme with SB-219994, were identified in this manner [19].
• OA challenge, with histamine antagonism (methapyrilene) resulted in uterine contractions which significantly raised myometrial tonus, presumably due to AA metabolites [20].

Gene context of Thenylpyramine

• In this study we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to investigate discrepant results between the National Institute of Environmental Health Sciences cDNA and Affymetrix oligo platforms used to evaluate hepatic gene expression changes in rats exposed to methapyrilene [21].
• Caldesmon cDNA platform hybridization results showed decreases in gene expression levels for the high-dose methapyrilene 7-day pooled samples compared with their controls [21].
• Altered distribution of hexokinase and glucokinase between parenchymal and nonparenchymal cells of rat liver after methapyrilene intoxication [22].
• Methapyrilene failed to induce formation of DNA adducts in L5178Y cell DNA at doses which induced mutations at the thymidine kinase locus [23].
• Methapyrilene is inactive in the hepatocyte-mediated Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase mutational assay [24].

Analytical, diagnostic and therapeutic context of Thenylpyramine

• The pathogenesis of hepatocellular tumors induced in F344 rats by the antihistaminic methapyrilene was investigated by light and electron microscopy in a serial sacrifice study [25].
• 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 [26].
• The major metabolite was isolated with reversed-phase HPLC and identified as methapyrilene N-oxide [27].
• Plasma and urine concentrations of methapyrilene by nitrogen-phosphorus gas-liquid chromatography [28].
• 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 [29].

References