116 research outputs found
Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo
At low doses, N-nitrosomethylethylamine (NMEA) selectively produces liver tumors in rats, whereas β-trideuterated NMEA also includes esophageal carcinomas under these conditions. Since deuteration is capable of retarding enzymic hydroxylation, these studies suggest that β-hydroxylation plays a significant role in the organ specificity of NMEA. To test the hypothesis that this metabolic pathway occurs in vivo to yield a hydroxyethylating intermediate, we have determined the extent of hydroxyethylation of hepatic DNA in male Fischer 344 rats following a single i.p. injection of [1-ethyl-14C]NMEA (6.3 mg/kg, 4 h survival). After hydrolysis in 0.1 M HCI, DNA purines were analysed by cation exchange chromatography. Of the major alkylpurines identified, 7-ethylguanine (7-etG) (6.7 μmol/mol guanine) and O6-ethylguanine (4.1 μmol/mol guanine) comprised 13 and 8% of the eluted radioactivity, respectively. 7-(2-HydroxyethyI)guanine (7-heG) was the only hydroxyethyl adduct detectable, and comprised less than 2% of the amount of 7-etG. 3-Ethylguanine and 3- and 7-ethyladenine were also identified as products of NMEA metabolism. Similar analyses were carried out on hepatic DNA from rats treated with N-nitrosodi[1-14C]ethylamine (6.9 mg/kg, 4 h survival). Only trace amounts of 7-heG could be detected. The very low concentrations of β-hydroxyethylated DNA bases observed suggest that this route of metabolism does not contribute significantly to the carcinogenicity of these compound
β-Deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus
While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its β-trideuterated derivative, N-nitroso([2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]- and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and ethylated purines in the DNA of various organs were determined by radiochromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-niethylguanine levelswerefoundtobereducedby ∽30%inliverandkldney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O6-Methlguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine In hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that β-trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissue
Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity
Glycosylated diazeniumdiolates of structure R2NN(O)dNO-R ′ (R ′ ) a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)dNO- ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8-4.6 as background for further developing both the protecting group application and the ability to target NO pharmacologically to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)dNO-GlcNAc (where R2N) diethylamino or pyrrolidin-l-yl and GlcNAc) N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity
Fifty Years of Diazeniumdiolate Research. From Laboratory Curiosity to Broad-Spectrum Biomedical Advances
Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics
ABSTRACT V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney
TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells
Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy
Immunotherapy with IL-2 and anti-CD40 induces the expression of NOS2 in tumor-associated macrophages, and its expression is required for the inhibition of tumor metastasis
Green tea intake is associated with urinary estrogen profiles in Japanese-American women
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