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PubMed1998

Exploratory studies on azole carboxamides as nucleobase analogs: thermal denaturation studies on oligodeoxyribonucleotide duplexes containing pyrrole-3-carboxamide.

In order to study base pairing properties of the amide group in DNA duplexes, a nucleoside analog, 1-(2'-deoxy-beta-D-ribofuranosyl)pyrrole-3-carboxamide, was synthesized by a new route from the ester, methyl 1-(2'-deoxy-3',5'-di-O-p -toluoyl-beta-D-erythro-pentofuranosyl)pyrrole-3-carboxylate, obtained from the coupling reaction between 1-chloro-2-deoxy-3,5-di-O -toluoyl-d-erythropentofuranose and methyl pyrrole-3-carboxylate by treatment with dimethylaluminum amide. 1-(2'-Deoxy-beta-D-ribofuranosyl)pyrrole-3-carboxamide was incorporated into a series of oligodeoxyribonucleotides by solid-phase phosphoramidite technology. The corresponding oligodeoxyribonucleotides with 3-nitropyrrole in the same position in the sequence were synthesized for UV comparison of helix-coil transitions. The thermal melting studies indicate that pyrrole-3-carboxamide, which could conceptually adopt either a dA-like or a dI-like hydrogen bond conformation, pairs with significantly higher affinity to T than to dC. Pyrrole-3-carboxamide further resembles dA in the relative order of its base pairing preferences (T >dG >dA >dC). Theoretical calculations on the model compound N-methylpyrrole-3-carboxamide using density functional theory show little difference in the preference for a syntau versus anti conformation about the bond from pyrrole C3 to the amide carbonyl. The amide groups in both the minimized antitau and syntau conformations are twisted out of the plane of the pyrrole ring by 6-14 degrees. This twist may be one source of destabilization when the amide group is placed in the helix. Another contribution to the difference in stability between the base pairs of pyrrole-3-carboxamide with T and pyrrole-3-carboxamide with C may be the presence of a hydrogen bond in the former involving an acidic proton (N3-H of T).

Azoles↗
PubMed1975

Formation and excretion of pyrrole-2-carboxylic acid. Whole animal and enzyme studies in the rat.

A corrected method for the measurement of pyrrole-2-carboxylate in rat urine was used in studies of its excretion under various experimental conditions. The findings implicated administered hydroxy-L-proline as a relatively efficient source of urinary pyrrole-2-carboxylate and tended to exclude administered L-proline as a significant direct source. Removal of aerobic gut flora had no influence on the excretion of pyrrole-2-carboxylate either endogenously or following hydroxy-L-proline administration. Related studied showed that rat kidney L-amino acid oxidase catalyzes oxidation of hydroxy-L-proline to delta1-pyrroline-4-hydroxy-2-carboxylate, which is converted to pyrrole-2-carboxylate on acidification of reaction mixtures. All findings were consistent with hydroxy-L-proline as the source of endogenous pyrrole-2-carboxylate excretion. Excretion patterns and labeling patterns were compared after administration of pyrrole-2-carboxylate or of hydroxy-proline epimers. From these data, the true excretion product of hydroxy-L-proline oxidation by L-amino acid oxidase appeared to be the unstable oxidation product, delta1-pyrroline-4-hydroxy-2-carboxylate, which is converted to pyrrole-2-carboxylate in urine. The capacity of homogenates of guinea pig kidney and human kidney to carry out oxidation of hydroxy-L-proline to pyrrole-2-carboxylate was much less than that of rat kidney, consistent with the lower levels of urinary pyrrole-2-carboxylate in these species. Experiments designed to examine the modest increase of pyrrole-2-carboxylate excretion after proline loads led to new observations on tissue levels of hydroxy-L-proline following proline administration and on the inhibition by L-proline of hydroxy-L-proline oxidase.

Alcohol Oxidoreductases↗
PubMed1986

Mechanisms of in vitro pyrrole adduct autoxidation in 2,5-hexanedione-treated protein.

The neurotoxic gamma-diketone, 2,5-hexanedione, reacts with axonal protein amine residues to form 2,5-dimethylpyrrole adducts. Current evidence implicates this reaction as the potentially critical step in gamma-diketone neurotoxicity, although it is unclear whether pyrrole formation per se is sufficient to induce neuropathy or whether secondary autoxidative reactions are also required. The present in vitro study examines aspects of pyrrole formation and the secondary phenomena of chromophore development and covalent protein crosslinking in 2,5-hexanedione-treated protein. p-Dimethylaminobenzaldehyde (DMAB)-detectable pyrrole concentrations decreased linearly with time when pyrrolylated bovine serum albumin (pyrrole-BSA) was incubated under air, but remained unchanged following N2 incubation. The air-induced decrease was accompanied by the appearance of chromophores and crosslinked protein. Covalent crosslinking of pyrrole-BSA was pH-dependent, with relatively increased intermolecular bridging at pH 7.4 as compared to pH 9.5. Chromophore formation and the loss in DMAB-detectable pyrrole were also accelerated at the lower pH. Autoxidative parameters were inhibited in the presence of a free radical scavenger (ascorbic acid) but induced by free radical initiators (potassium persulfate and 2,2'-azobis[2-amidinopropane hydrochloride]). In vitro incubation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of combinations of bovine serum albumin, ribonuclease, pyrrole-BSA, and pyrrolylated ribonuclease revealed that the intermolecular crosslinking pathway was mediated by pyrrole-pyrrole bridging. These findings demonstrate that the secondary autoxidative phenomena following pyrrole adduct formation in gamma-diketone-treated protein proceed via pH-dependent, free radical-mediated mechanisms. If similar mechanisms are present in vivo, the results also suggest that intermolecular covalent crosslinking of pyrrolylated axonal protein may be less widespread and more specific than previously thought.

Animals↗
PubMed1994

Purification and characterization of a pyrrole-2-carboxylate oxygenase from Arthrobacter strain Py1.

Pyrrole-2-carboxylate oxygenase was purified 8.2-fold to homogeneity from Arthrobacter strain Py1 grown on pyrrole-2-carboxylate as sole carbon, nitrogen, and energy source. FAD and dithioerythritol had to be present during the purification procedure to stabilize the enzyme activity. The molecular mass of the pyrrole-2-carboxylate oxygenase was about 160 kDa by gel filtration chromatography and native gradient PAGE, only one polypeptide of about 60 kDa was present after SDS-PAGE. The FAD content was 2.7 to 3.6 mol FAD per enzyme (160 kDa). The non-covalently bound FAD of the pyrrole-2-carboxylate oxygenase was reduced by NADH and reoxidized by oxygen and pyrrole-2-carboxylate. The enzyme exhibited a narrow substrate specificity. Besides pyrrole-2-carboxylate, only pyrrole, pyrrole-2-aldehyde, and indole-2-carboxylate stimulated the oxygen consumption at a very low rate. The enzyme activity was strongly reduced by different sulfhydryl group inhibitors, but it could be restored by 2-mercaptoethanol or dithiothreitol. The content of pyrrole-2-carboxylate oxygenase was about 6% of the soluble protein as determined by antibodies raised against the enzyme. No cross reacting material was present in other bacteria also able to degrade pyrrole-2-carboxylate. A low amount of the enzyme was present in uninduced cells of Arthrobacter strain Py1, although the enzymatic activity was below the detection limit. The N-terminal amino acid sequence of the enzyme did not contain the consensus sequence GXGXXG found to be present close to the N-terminus of many flavin-dependent monoxygenases sequenced so far.

Amino Acid Sequence↗
PubMed2004

Determination of pyrrolized phospholipids in oxidized phospholipid vesicles and lipoproteins.

The Ehrlich reaction was optimized to determine pyrrolized phospholipids produced as a consequence of oxidative stress. The procedure consisted of the treatment of the modified phospholipids with p-(dimethylamino)benzaldehyde at a controlled acidity temperature and the spectrophotometric determination of adducts produced. The extinction coefficient of Ehrlich adducts was calculated by using 1-[1-(2-hydroxyethyl)-1H-pyrrol-2-yl]propan-1-ol (compound 1) as standard and was 56,500 M(-1)cm(-1). The response was linear and reproducible within the range of 0.051-7.65 microM of compound 1. When the assay was applied to determination of pyrrole content in ethanolamine incubated in the presence of 0.25-1mM of 4,5(E)-epoxy-2(E)-heptenal, the complete conversion of the aldehyde into the pyrrole ring was observed and the results obtained were similar to those found when compound 1 was determined by gas chromatography. When phosphatidylethanolamine was incubated in the presence of 0.5-40 mM of 4,5(E)-epoxy-2(E)-heptenal, the phospholipid was pyrrolized similarly to ethanolamine, although there was not a quantitative conversion and the amount of pyrroles produced depended on the pH of the media. Pyrrolized phospholipids were also produced when phosphatidylethanolamine multilamellar vesicles where oxidized in the presence of either Fe(3+)/ascorbic acid or ABAP (2,2'-azobis(2-methylpropionamide) dihydrochloride) and when high-density lipoproteins were incubated in the presence of Cu(2+), thereby confirming that phospholipid pyrrolization is a common consequence of oxidative stress and that Ehrlich adducts may be valid for determining this pyrrolization.

Chromatography, High Pressure Liquid↗
PubMed2003

Effect of the pyrrole polymerization mechanism on the antioxidative activity of nonenzymatic browning reactions.

The present investigation was undertaken to study how the antioxidative activity (AA) of nonenzymatic browning reactions is changing at the same time that the browning (by the pyrrole polymerization mechanism) is being produced. The antioxidative activities of eight model pyrroles (pyrrole, 1-methylpyrrole, 2,5-dimethylpyrrole, 1,2,5-trimethylpyrrole, 2-acetylpyrrole, 2-acetyl-1-methylpyrrole, pyrrole-2-carboxaldehyde, and 1-methyl-2-pyrrolecarboxaldehyde) as well as the browning reaction of 2-(1-hydroxyethyl)-1-methylpyrrole (HMP) and the dimer (DIM) produced during HMP browning were determined. The results obtained suggest that the AAs observed in nonenzymatic browning reactions are the result of the AAs of the different oxidized lipid/amino acid reaction products formed. Thus, the different pyrrole derivatives produced in these reactions had different AAs, and the highest AAs were observed for alkyl-substituted pyrroles without free alpha-positions. Because some of these pyrrole derivatives are implicated in nonenzymatic browning production and this browning production implies the loss of hydroxyl groups and the transformation of some pyrroles with one type of substitution into others, changes in AA during browning production were observed, and the resulting DIM derivative was more antioxidant than HMP or higher polymers. These results explain the AA observed in fatty acid/protein mixtures after slight oxidation and suggest that, when the pyrrole polymerization mechanism is predominant, slightly browned samples may be more antioxidant than samples in which nonenzymatic browning has been highly developed.

Antioxidants↗
PubMed2001

Novel 2,5-hexanedione analogues. Substituent-induced control of the protein cross-linking potential and oxidation susceptibility of the resulting primary amine-derived pyrroles.

The neurotoxic gamma-diketone, 2,5-hexanedione (2,5-HD), induces neurofilamentous swellings at prenodal sites in proximal axons as a consequence of pyrrolation of lysine epsilon-amino groups on neurofilament proteins. However, there is disagreement as to whether pyrrole formation and the associated alteration of noncovalent interactions is sufficient to cause neurofilament accumulation, or whether pyrrole autoxidation and subsequent protein-protein cross-linking is an obligatory event. To investigate gamma-diketones that might form pyrroles inert to autoxidative-induced cross-linking, we synthesized 1,1,1-trifluoro-2,5-hexanedione, 3-(trifluoromethyl)-2,5-hexanedione (3-TFMHD), and two 3-(dialkylaminocarbonyl)-2,5-diketones and assessed their rates of pyrrole formation with amines, the oxidation susceptibility of the resulting pyrroles, and the protein cross-linking potential in vitro, relative to those of 3-methyl-2,5-hexanedione. 1,1,1-Trifluoro-2,5-hexanedione does not form pyrroles, but the three 2,5-HD analogues with an electron-withdrawing 3-substituent all rapidly formed pyrroles that were inert to autoxidation. Although 3-TMFHD nonetheless still induced cross-linking of ribonuclease A, by a nonoxidative mechanism independent of the pyrrole, the two 3-(dialkylaminocarbonyl)-2,5-diketones did not exhibit any protein cross-linking. As these two gamma-diketones possess aqueous-organic partitioning properties similar to those of 2,5-HD, they should serve as useful mechanistic probes in further studies.

Axons↗
PubMedDate not supplied

Formation and structure of cross-linking and monomeric pyrrole autoxidation products in 2,5-hexanedione-treated amino acids, peptides, and protein.

2,5-Hexanedione (2,5-HD) is the neurotoxic gamma-diketone metabolite of the industrial solvent n-hexane. Substantial evidence indicates that 2,5-HD reacts with neurofilament protein lysine epsilon-amines to yield 2,5-dimethylpyrrole adducts and that this reaction is critical to the mechanism of toxicity. Alkylpyrroles are susceptible to autoxidative dimerization, a process that has also been suggested as an obligatory step in 2,5-HD neuropathy. In the present study, we characterized pyrrole autoxidation products of a 2,5-HD-treated lysine analogue and of a model, lysine-containing dipeptide and examined mechanistic aspects of pyrrole-mediated protein cross-linking. Incubation of 2,5-HD with N alpha-acetyllysine or the dipeptide N alpha-acetylglycyllysine methyl ester in physiological buffer (pH 7.4) under oxidative conditions resulted in time-dependent formation of the N epsilon-pyrrole derivative and two major pyrrole autoxidation products, as demonstrated by HPLC, on-line thermospray MS, and UV photodiode array detection. An autoxidative pyrrole dimer containing a methylene bridge between C-2 of one pyrrole ring and C-3 of a second ring was characterized by thermospray MS and 1H-NMR spectroscopy. 13C-NMR spectroscopy provided evidence for an identical pyrrole-to-pyrrole bridge in autoxidized, pyrrolylated ribonuclease (RNase). MS analysis also revealed a second major product--a stable, oxygen-containing monomeric pyrrole derivative. This product exhibited a UV absorbance maximum (lambda max = 355 nm) consistent with extended conjugation. Polymerization of pyrrolylated acetyllysine was accelerated by persulfate, a free-radical initiator, and inhibited by ascorbate, an antioxidant.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1981

Relation of structural features to pyrrolic metabolites in livers of rats given pyrrolizidine alkaloids and derivatives.

Levels of pyrrolic metabolites have been measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. Structural and chemical features favouring the formation of such metabolites have been defined. The most important of these were: steric hindrance or chemical properties giving resistance to ester hydrolysis; lipophilic character, allowing access to hepatic microsomal enzymes; a conformation favoring microsomal oxidation of the pyrroline ring in preference to N-oxidation. In addition, the presence of ester groups gave the resulting pyrroles high chemical reactivity, leading to tissue binding. Amounts of pyrroles bound to liver were very low when animals were given either highly water soluble pyrrolizidine derivatives, including non-esterified bases or more-lipophilic esters if these were easily hydrolysed. Compounds prone to hydrolysis gave increased pyrrole levels in rats pretreated to deplete their esterase activity. Whereas heliotridine-based alkaloids usually give more pyrrole than similar retronecine esters, heliotridine ditiglate gave less pyrrole than retronecine ditiglate because the former was more open to hydrolytic attack. Among the carboxylic diesters, the cyclic retronecine diesters, in which the pyrrolizidine nucleus is more exposed to oxidative metabolism, gave the highest pyrrole levels in rats. Liver pyrrole measurements are useful for studying relationships between molecular structure, metabolism and toxicity of pyrrolizidine derivatives. They can be used for screening alkaloids for potential toxicity and for assessing dose levels suitable for toxicity tests when limited material is available.

Animals↗
PubMed1983

Pyrrolic and N-oxide metabolites formed from pyrrolizidine alkaloids by hepatic microsomes in vitro: relevance to in vivo hepatotoxicity.

An analytical method of improved sensitivity has enabled measurements to be made of N-oxide as well as pyrrolic metabolites formed from a range of unsaturated pyrrolizidine alkaloids in hepatic microsome preparations. Using microsomes from livers of phenobarbitone-pretreated male Fischer rats, all 13 alkaloids tested were metabolised to both N-oxides and pyrroles. The most lipophilic alkaloids gave enhanced rates of metabolism. No consistent relationship existed between rates of N-oxide and of pyrrole formation. The two pathways appeared to be independent. The ratio of N-oxide to pyrrolic metabolites varied, depending on the type of ester: it was highest for 'open' diester alkaloids, lowest for 12 membered macrocyclic diesters and for monoesters. Steric hindrance by the acid moiety could account for these differences, by affecting the balance between microsomal oxidation of the amino alcohol moiety at the nitrogen and C8 positions respectively and could explain the high pyrrole yields given by some macrocyclic diesters. The levels of pyrrolic metabolites bound to liver tissues and responsible for hepatotoxicity in rats given pyrrolizidine alkaloids, did not necessarily reflect the rates of formation of such metabolites measured in vitro. In the animal additional factors could influence the formation and tissue binding of pyrrolic metabolites, including the detoxication of alkaloids by hydrolysis and the chemical reactivity and stability of the toxic metabolites. A comparison of heliotridine esters with retronecine esters showed that the 7-hydroxyl or -ester configuration had a relatively small influence on the balance between formation of pyrrolic metabolites and detoxication by N-oxidation. The results did not support any hypothesis that heliotridine esters should generally be more hepatotoxic than analogous retronecine esters. The structure of the acid moiety was likely to have at least as much influence on toxicity as the base configuration.

Animals↗
PubMedDate not supplied

Pyrrole oxidation and protein cross-linking as necessary steps in the development of gamma-diketone neuropathy.

It has been well documented that the gamma-diketone HD1 is the ultimate toxic metabolite of n-hexane. Furthermore, it has been shown that the pathogenetic mechanism by which HD exerts its neurotoxic effects is through binding to protein lysly residues and cyclization to pyrroles. The present study sought to determine whether the presence of pyrrole residues on NF1 proteins is sufficient to cause the NF-filled axonal swellings associated with n-hexane and other gamma-diketone neuropathies or whether pyrrole oxidation and protein cross-linking also have to occur in order for neurotoxicity to develop. We synthesized the HD analogue AcHD1 and assessed its rate of pyrrole formation in vitro, the ease of oxidation of its resulting pyrroles, and its ability to cross-link proteins in vitro. The in vivo effects of AcHD on rats were examined following daily ip1 injections. AcHD was found to have a rate of pyrrole formation comparable to that of the potent HD analogue DMHD1 at 35 degrees C. The pyrrole derived from AcHD was more resistant to oxidation than that derived from the neurotoxic compound HD. AcHD did not cross-link proteins in vitro. Pyrrole derivatives were demonstrated on hemoglobin isolated from animals treated with HD, DMHD, and AcHD. Cross-linked spectrin was detected in animals treated with HD and DMHD but not with AcHD. Rats receiving 0.1 or 0.25 mmol of AcHD/kg/day did not reach the end point of hindlimb paralysis observed in the gamma-diketone neuropathies, and the NF-filled axonal swellings seen following exposure to the neurotoxic gamma-diketones were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Formation and stability of pyrrole adducts in the reaction of levuglandin E2 with proteins.

Levuglandin (LG) E2 is rapidly sequestered by covalent binding with proteins. The reaction of LGE2 with a protein in neutral aqueous solution exhibits two phases. A metastable adduct rapidly accumulates initially. In the second phase, a protein-bound pyrrole is generated. Pyrrole formation and stability were monitored with an immunoassay using antibodies that were raised against a stable isostere. That LG-derived pyrroles are the major products (> 76%) of the LGE2-protein reaction is suggested by the level of antibody binding found for LG-protein adducts compared with that found for a pyrrole derived from LGE2 and 6-amino-1-hexanol. Because the initial metastable LG-protein adduct is a reactive electrophile, it can be trapped with amines, such as glycine, to give stable ternary adducts that do not cross-react with the antibodies. Although highly alkylated pyrroles are chemically sensitive compounds, the protein-bound LG-derived pyrrole appears to be stable in aqueous solution at pH 7.4. Thus, it shows no decrease in immunoreactivity over several weeks. This discovery leads to the expectation that such pyrroles will accumulate in vivo, especially in proteins that do not turn over rapidly. Thus, the LG-derived protein-bound pyrrole may be a useful marker of oxidative lipid damage, and an immunoassay for this post-translational protein modification can be exploited as a mild, sensitive method for detecting and quantifying the generation of LGs in chronic inflammatory states.

Animals↗
PubMed2003

Pyrrole-appended derivatives of O-confused oxaporphyrins and their complexes with nickel(II), palladium(II), and silver(III).

Condensation of 2,4-bis(phenylhydroxymethyl)furan with pyrrole and p-toluylaldehyde formed, instead of the expected 5,20-diphenyl-10,15-di(p-tolyl)-2-oxa-21-carbaporphyrin, a pyrrole addition product [(H,pyr)OCPH]H(2); this product can formally be considered as an effect of hydrogenation of 3-(2'-pyrrolyl)-5,20-diphenyl-10,15-di(p-tolyl)-2-oxa-21-carbaporphyrin ([(pyr)OCPH]H). The new oxacarbaporphyrinoid presents the (1)H NMR spectroscopy features of an aromatic molecule, including the upfield shift of the inner H21 atom. Insertion of NiCl(2) or PdCl(2) into [(H,pyr)OCPH]H(2) gave two structurally related organometallic complexes, [(pyr)OCP]Ni(II)] and [(pyr)OCP]Pd(II)], in which the metal ions are bound by three pyrrolic nitrogens and the trigonally hybridized C21 atom of the inverted furan. The reaction of [(H,pyr)OCPH]H(2) with silver(I) acetate yields a stable Ag(III) complex [(C(2)H(5)O,pyr)OCP]Ag(III)] substituted at the C3 position by the ethoxy and pyrrole moieties. The macrocyclic frame of [(H,pyr)OCPH]H(2) is conserved. Addition of trifluoroacetic acid to [(C(2)H(5)O,pyr)OCP]Ag(III)] yielded a new aromatic complex [(pyr)OCP]Ag(III)](+). The structures of [(pyr)OCP]Ni(II)] and [(C(2)H(5)O,pyr)OCP]Ag(III)] have been determined by X-ray crystallography. In both molecules the macrocycles are only slightly distorted from planarity and the nickel(II) and silver(III) are located in the NNNC plane. The dihedral angle between the macrocyclic and appended-pyrrole planes of [(pyr)OCP]Ni(II)] reflects the biphenyl-like arrangement with the NH group pointing out toward the adjacent phenyl ring on the C5 position. Tetrahedral geometry around the C3 atom was detected for [(C(2)H(5)O,pyr)OCP]Ag(III)]. The Ni[bond]C and Ag[bond]C bond lengths are similar to other nickel(II) or silver(III) carbaporphyrinoids where the trigonal carbon atom coordinates the metal ion. The trend detected in the (13)C chemical shifts for the appended-pyrrole resonances has been rationalized by the extent of effective conjugation between the macrocycle and the appended pyrrole moiety controlled by the hybridization of the C3 atom and the metal ion oxidation state. The dianionic or trianionic macrocyclic core of the pyrrole-appended derivatives is favored to match the oxidation state of nickel(II), palladium(II), or silver(III), respectively.

Journal Article↗
PubMed1993

Enhanced glutathione S-transferase 7-7 expression in rat hepatic cytosol following treatment with pyrrole.

Rat hepatic GST 7-7 expression in cytosol and in the S-hexylglutathione-agarose affinity purified fraction of cytosol from saline- (control) and pyrrole-treated animals was examined using metabolic activity, SDS-PAGE, immunoblot, and HPLC analyses. Metabolic activity of hepatic cytosol from pyrrole-treated animals was assayed using the substrates 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and acrolein, and an approximately 1.5-, 1.2-, and 1.3-fold increase, respectively, was monitored in the rate of GST-catalyzed substrate conjugation to reduced glutathione. SDS-PAGE and immunoblot analysis using Class Pi GST-specific IgG confirmed that the GST 7 subunit was expressed in hepatic cytosol and in the affinity purified fractions from pyrrole-treated rats. In contrast, the GST 7 subunit was below the limit of detection in hepatic cytosol of saline-treated animals. HPLC analysis demonstrated the presence of the GST 7 subunit in the affinity purified fraction from pyrrole-treated rat hepatic tissue and showed that the level of this subunit was increased approximately 8-fold relative to the barely detectable level present in control tissue. N-terminal amino acid sequencing analysis confirmed the identity of the HPLC peak as GST 7-7. GST subunits 3, 1a, and 1b were elevated approximately 1.7-, 2.0-, and 2.4-fold respectively, in response to pyrrole treatment. These data provide evidence that pyrrole treatment results in de novo expression of GST 7-7 in rat hepatic tissue and suggest that pyrrole-containing compounds potentially generated during disease and/or altered heme metabolism, or those ingested in food products, may alter GST expression in hepatic tissue.

Animals↗
PubMed1995

Linoleic acid oxidation in the presence of amino compounds produces pyrroles by carbonyl amine reactions.

The reactions of 13-hydroperoxy-9(Z),11(E)-octadecadienoic acid (13-LOOH) and its degradation product 4,5(E)-epoxy-2(E)-decenal with butylamine and lysine were studied to determine whether pyrrole derivatives isolated in model reactions were produced in complex systems involving hydroperoxides. Incubated reaction mixtures were studied by gas chromatography coupled with mass spectrometry or high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS), and some compounds were isolated by column chromatography or semipreparative HPLC, and identified by 1H- and 13C-nuclear magnetic resonance spectroscopy and MS. The reaction of epoxyalkenals with amino groups produced two types of pyrrole derivatives: 1-substituted 2-(1'-hydroxyalkyl)pyrroles and 1-substituted pyrroles. 1-Substituted 2-(1'-hydroxyalkyl)pyrroles were responsible for the development of color and fluorescence by a polymerization reaction, which implied the formation of dipyrrylmethanes and dipyrrylmethenes. 1-Substituted pyrroles were final products in these reactions and their determination might be used as an index of oxidative stress. The above reactions were also observed between 13-LOOH and amino compounds, and suggested that the pyrrole polymerization mechanism plays a role in the fluorescence observed by reaction of hydroperoxides and amino groups.

Aldehydes↗
PubMed1985

The ability of bifunctional and monofunctional pyrrole compounds to induce sister-chromatid exchange (SCE) in human lymphocytes and mutations in Salmonella typhimurium.

The ability to induce sister-chromatid exchange (SCE) in human lymphocytes and mutations in Salmonella typhimurium has been assessed for 4 pyrrole compounds. Three of the compounds, 2,3-bishydroxymethyl-1-methylpyrrole (BHMP), 2-hydroxymethyl-1-methylpyrrole (2HMP) and 3-hydroxymethyl-1-methylpyrrole (3HMP) are synthetic pyrrolic alcohols; the fourth compound, dehydroretronecine (DHR) is a metabolite of several naturally occurring pyrrolizidine alkaloids. The activity of these compounds was compared with that of mitomycin C (MMC) and decarbamoyl mitomycin C (DCMMC), chemicals related structurally to the pyrrole compounds. All 6 compounds caused an increase in the numbers of SCEs. Whereas the bifunctional pyrroles, DHR and BHMP, and the mitomycins, MMC and DCMMC, increased levels of SCEs by 8-12 times control levels, the monofunctional pyrroles gave increases of only 2 times. Three of the 4 pyrrole compounds (DHR, BHMP and 3HMP) induced mutations in the Salmonella typhimurium base substitution strain TA92, the fourth (2HMP) was not found to be mutagenic in any of the 8 strains used. The mitomycins induced mutations in the frameshift strain TA94 in addition to the base substitution strain TA92, with DCMMC always more mutagenic and less cytotoxic than MMC. All bifunctional compounds induced more mutations and were less cytotoxic in strains containing an efficient excision-repair system. With the pyrrole compounds numbers of SCEs and mutations were only increased when using chemical concentrations significantly higher than those required for the mitomycins: more than twice as high to produce significant numbers of SCEs and more than 100 times as high to produce equal numbers of mutations.

Humans↗
PubMed2000

Contribution of pyrrole formation and polymerization to the nonenzymatic browning produced by amino-carbonyl reactions.

Recent studies have hypothesized that pyrrole formation and polymerization may be contribute to the nonenzymatic browning produced in both oxidized lipid/protein reactions and the Maillard reaction. To develop a methodology that would allow investigation of the contribution of this browning mechanism, the kinetics of formation of color, fluorescence, and pyrrolization in 4, 5(E)-epoxy-2(E)-heptenal/lysine and linolenic acid/lysine model systems were studied. In both cases similar kinetics for the three measurements were observed at the two temperatures assayed (37 and 60 degrees C), and there was a high correlation among color, fluorescence, and pyrrolization measurements obtained as a function of incubation time. Because the color and fluorescence production in the 4,5(E)-epoxy-2(E)-heptenal/lysine system is a consequence of pyrrole formation and polymerization, the high correlations observed with the unsaturated fatty acid also suggest a contribution of the pyrrole formation and polymerization to the development of color and fluorescence observed in the fatty acid/lysine system. Although the contribution of other mechanisms cannot be discarded, all of these results suggest that when the pyrrole formation and polymerization mechanism contributes to the nonenzymatic browning of foods, a high correlation among color, fluorescence, and pyrrolization measurements should be expected.

Amines↗
PubMed2001

Structural characterization of pyrrolic cross-links in collagen using a biotinylated Ehrlich's reagent.

The structures of pyrrolic forms of cross-links in collagen have been confirmed by reacting collagen peptides with a biotinylated Ehrlich's reagent. This reagent was synthesized by converting the cyano group of N-methyl-N-cyanoethyl-4-aminobenzaldehyde to a carboxylic acid, followed by conjugation with biotin pentyl-amine. Derivatization of peptides from bone collagen both stabilized the pyrroles and facilitated selective isolation of the pyrrole-containing peptides using a monomeric avidin column. Reactivity of the biotinylated reagent with collagen peptides was similar to that of the standard Ehrlich reagent, but heat denaturation of the tissue before enzyme digestion resulted in the loss of about 50% of the pyrrole cross-links. Identification of a series of peptides by mass spectrometry confirmed the presence of derivatized pyrrole structures combined with between 1 and 16 amino acid residues. Almost all of the pyrrole-containing peptides appeared to be derived from N-terminal telopeptide sequences, and the nonhydroxylated (lysine-derived) form predominated over pyrrole cross-links derived from helical hydroxylysine.

Avidin↗