Pyridine nucleotides. 3. Response of dog thyroid pyridine nucleotides to hormonal control.
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Animals↗
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Interaction between ferredoxin and ferredoxin nicotinamide adenine dinucleotide phosphate reductase in pyridine nucleotide photoreduction and some partial reactions. II. Complex formation between ferredoxin and ferredoxin nicotinamide adenine dinucleotide phosphate reductase and its relevance to pyridine nucleotide photoreduction.
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Chemical Phenomena↗
Antibacterial borazaro derivatives. I. 5-Arylsulphonyl-4-hydroxy-4,5-borazarothieno(2,3-c)pyridines and 6-arylsulphonyl-7-hydroxy-7,6-borazarothieno(3,2-c)pyridines.
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Boranes↗
Pharmacological evaluation of some new 2-substituted pyridine derivatives.
In the present study, a series of 2-substituted-pyridines were synthesized and characterized by IR, (1)H-NMR and Elemental Analysis. The compounds were assayed against seizures induced by maximal electro shock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg/kg, antihistaminic and cardiac activity were also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 2-(2'-piperazino-ethanoxy)pyridine, 2-(3'-morpholino-2'-hydroxypropyloxy)pyridine, 2-(3'-piperidino-2'-hydroxypropyloxy)pyridine and 2-(3'-piperazino-2'-hydroxypropyloxy)pyridine were most active of the series against MES-induced seizures. Compounds 2-(2'-piperazino-ethanoxy)pyridine, 2-(2'-phenylamino-ethanoxy)pyridine, 2-(3'-imidazolo-2'-hydroxypropyloxy)pyridine, 2-(3'-methylamino-2'-hydroxypropyloxy)pyridine and 2-(3'-piperidino-2'-hydroxypropyloxy)pyridine exhibited significant decrease in the elevated motor activity at the dose of 50 mg/kg. Remarkable sympathetic blocking activity was observed with 2-(3'-piperazino-2'-hydroxypropyloxy)pyridine, 2-(3'-piperidino-2'-hydroxypropyloxy)pyridine and 2-(3'-imidazolo-2'-hydroxypropyloxy)pyridine only. Compounds 2-(2'-morpholino-ethanoxy)pyridine, 2-(2'-piperidino-ethanoxy)pyridine, 2-(2'-piperazino-ethanoxy)pyridine, 2-(2'-imidazolo-ethanoxy)pyridine, 2-(2'-diphenylamino-ethanoxy)pyridine, 2-(2'-diethanolamino-ethanoxy)pyridine, 2-(2'-phenylamino-ethanoxy)pyridine and 2-(2'-(4"-hydroxy)phenylamino-ethanoxy)pyridine exhibited significant blocking of histamine induced contraction on guinea pig ileum.
Animals↗
NTP Toxicology and Carcinogenesis Studies of Pyridine (CAS No. 110-86-1) in F344/N Rats, Wistar Rats, and B6C3F1 Mice (Drinking Water Studies).
Pyridine is used as a denaturant in alcohol and anti freeze mixtures, as a solvent for paint, rubber, and polycarbonate resins, and as an intermediate in the manufacture of insecticides, herbicides, and fungicides. It is used in the production of piperidine, an intermediate in the manufacture of rubber and mepiquat chloride, and as an intermediate and solvent in the preparation of vitamins and drugs, dyes, textile water repellants, and flavoring agents in food. Pyridine was nominated for study because of its large production volume and its use in a variety of food, medical, and industrial products. Male and female F344/N rats, male Wistar rats, and male and female B6C3F1 mice were exposed to pyridine (approximately 99% pure) in drinking water for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 13-WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female F344/N rats were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 5, 10, 25, 55, or 90 mg pyridine/kg body weight). Two females exposed to 1,000 ppm died during week 1. Final mean body weights of 1,000 ppm males and females and 500 ppm females were significantly less than controls. Water consumption by female rats exposed to 1,000 ppm was less than that by controls. At study termination, evidence of anemia persisted in the 500 and 1,000 ppm males and all exposed groups of females. There was evidence of hepatocellular injury and/or altered hepatic function demonstrated by increased serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations in 500 and 1,000 ppm rats. The estrous cycle length of 1,000 ppm females was significantly longer than that of the controls. Liver weights of males and females exposed to 250 ppm or greater were significantly greater than controls. In the liver, the incidences of centrilobular degeneration, hypertrophy, chronic inflammation, and pigmentation were generally increased in 500 and 1,000 ppm males and females relative to controls. In the kidney, the incidences of granular casts and hyaline degeneration (hyaline droplets) were significantly increased in 1,000 ppm males and slightly increased in 500 ppm males; these lesions are consistent with 2u-globulin nephropathy. Additionally, there were increased incidences and/or severities of protein casts, chronic inflammation, mineralization, and regeneration primarily in 500 and 1,000 ppm males. 13-WEEK STUDY IN MALE WISTAR RATS: Groups of 10 male Wistar rats were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 5, 10, 30, 60, or 100 mg/kg). One male rat exposed to 500 ppm died during week 1. Final mean body weights of rats exposed to 250, 500, or 1,000 ppm were significantly less than those of the controls. Water consumption by rats exposed to 1,000 ppm was lower than that by controls. There was evidence of hepatocellular injury and/or altered hepatic function in the 500 and 1,000 ppm groups, similar to that observed in the 13-week study in F344/N rats. Incidences of centrilobular degeneration, hypertrophy, chronic inflammation, and pigmentation in the liver of rats exposed to 500 or 1,000 ppm were significantly increased relative to controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 10, 20, 50, 85, or 160 mg/kg for males and 10, 20, 60, 100, or 190 mg/kg for females). One female mouse exposed to 250 ppm died during week 2. Final mean body weights of female mice exposed to 1,000 ppm were significantly less than those of controls. Water consumption by exposed female mice was lower than that by controls at week 1 but generally slightly higher than controls at week 13. Sperm motirm motility in exposed male mice was significantly decreased relative to controls. Liver weights were significantly increased relative to controls in males exposed to 100 ppm or greater and in 250 and 500 ppm females. No chemical-related lesions were observed in male or female mice. 2-YEAR STUDY IN F344/N RATS: Groups of 50 male and 50 female F344/N rats were exposed to pyridine in drinking water at concentrations of 0, 100, 200, or 400 ppm (equivalent to average daily doses of 7, 14, or 33 mg/kg) for 104 (males) or 105 (females) weeks. Survival, Body Weights, and Water Consumption Survival of exposed males and females was similar to that of controls. Mean body weights of 400 ppm males and females were generally less than those of the controls throughout the study, and those of 200 ppm males and females were less during the second year of the study. Water consumption by males and females exposed to 200 or 400 ppm was generally greater than that by controls. Pathology Findings Incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in male rats exposed to 400 ppm were significantly increased compared to controls and exceeded the historical control ranges. The findings from an extended evaluation (step section) of the kidneys did not reveal additional carcinomas, but additional adenomas were observed in each group of males. In the standard evaluation, an increased incidence of renal tubule hyperplasia was observed in 400 ppm males compared to controls. Incidences of mononuclear cell leukemia in female rats were significantly increased in the 200 and 400 ppm groups, and the incidence in the 400 ppm group exceeded the historical control range. Exposure concentration-related nonneoplastic liver lesions were observed in males and females, and the incidences were generally increased in groups exposed to 400 ppm. These included centrilobular cytomegaly, cytoplasmic vacuolization, periportal fibrosis, fibrosis, centrilobular degeneration and necrosis, and pigmentation. Bile duct hyperplasia occurred more often in exposed females than in controls. 2-YEAR STUDY IN MALE WISTAR RATS: Groups of 50 male Wistar rats were exposed to pyridine in drinking water at concentrations of 0, 100, 200, or 400 ppm (equivalent to average daily doses of 8, 17, or 36 mg/kg) for 104 weeks. Survival, Body Weights, and Water Consumption Survival of rats exposed to 200 or 400 ppm was significantly less than that of the controls. Mean body weights of rats exposed to 100, 200, or 400 ppm were significantly less than controls. Water consumption was similar by control and exposed rats. Pathology Findings The incidence of testicular interstitial cell adenoma in rats exposed to 400 ppm was significantly increased compared to controls. Incidences of interstitial cell hyperplasia were observed in control and exposed groups and were slightly, but not significantly, increased in rats exposed to 200 or 400 ppm. Severity of nephropathy was marked in all groups, and additional evidence of kidney disease, including mineralization in the glandular stomach, parathyroid gland hyperplasia, and fibrous osteodystrophy, was observed in 100 and 200 ppm rats. The incidences of hepatic centrilobular degeneration and necrosis, fibrosis, periportal fibrosis, and/or pigmentation were increased in one or more exposed groups. 2-YEAR STUDY IN MICE: Groups of 50 male B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 250, 500, or 1,000 ppm (equivalent to average daily doses of 35, 65, or 110 mg/kg) for 104 weeks, and groups of 50 female B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 125, 250, or 500 ppm (equivalent to average daily doses of 15, 35, or 70 mg/kg) for 105 weeks. Survival, Body Weights, and Water Consumption Survival of exposed males and females was similar to that of the controls. Mean body weights of 250 and 500 ppm females were less than controls. Water consumption by males exposed to 250 or 500 ppm was generally greater than that by controls during the last year of the study; male mice exposed to 1,000 ppm consumed less water than controls throughout the study. Water consumption by exposed females was generally lower than that by controls during the first year of the study, but greater than controls during the second year. Pathology Findings Hepatocellular neoplasms, including hepatoblastomas, in exposed male and female mice were clearly related to pyridine exposure. Additionally, many mice had multiple hepatocellular neoplasms. The incidences of hepatocellular neoplasms in exposed males and females generally exceeded the historical control ranges for drinking water studies. Neoplasms from control mice, 1,000 ppm males, and 500 ppm females were negative when stained for p53 protein. GENETIC TOXICOLOGY: Pyridine was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 or in L5178Y mouse lymphoma cells, with or without S9 metabolic activation, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. Pyridine was tested for induction of sex-linked recessive lethal mutations in adult male Drosophila melanogaster, and mixed results were obtained. In one experiment, administration by injection gave negative results, but feeding produced an equivocal response. A second experiment generated negative results by injection and feeding. A third experiment showed significant increases in sex-linked recessive lethal mutations in flies treated with pyridine by injection but not by feeding. Overall, results of the sex-linked recessive lethal mutations test in Drosophila melanogaster were considered negative by feeding and equivocal by injection. Results of a single reciprocal translocation test in male Drosophila melanogaster were negative. No induction of chromosomal aberrations or micronuclei was noted in bone marrow cells of male mice administered pyridine via intraperitoneal injection. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was some evidence of carcinogenic activity of pyridine in male F344/N rats based on increased incidences of renal tubule neoplasms. There was equivocal evidence of carcinogenic activity of pyridine in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was equivocal evidence of carcinogenic activity in male Wistar rats based on an increased incidence of interstitial cell adenoma of the testis. There was clear evidence of carcinogenic activity of pyridine in male and female B6C3F1 mice based on increased incidences of malignant hepatocellular neoplasms. In F344/N rats, exposure to pyridine resulted in increased incidences of centrilobular cytomegaly and degeneration, cytoplasmic vacuolization, and pigmentation in the liver of males and females; periportal fibrosis, fibrosis, and centrilobular necrosis in the liver of males; and bile duct hyperplasia in females. In male Wistar rats, pyridine exposure resulted in increased incidences of centrilobular degeneration and necrosis, fibrosis, periportal fibrosis, and pigmentation in the liver, and, secondary to kidney disease, mineralization in the glandular stomach and parathyroid gland hyperplasia. Synonyms: Azabenzene, azine
Journal Article↗
Simultaneous utilization of pyridine and fructose by Rhodococcus opacus UFZ B 408 without an external nitrogen source.
A bacterium classified as Rhodococcus opacus, which is able to use pyridine (a potentially growth-inhibiting substrate) as its sole source of carbon, energy and nitrogen, was isolated. In a carbon-limited chemostat culture, the kinetics was determined for growth on both pyridine and a mixture of pyridine and fructose (9 mM/22.15 mM). With growth on pyridine, stable steady states were achieved up to dilution rates of about 0.1 h-1. A further increase in the dilution rate resulted in the progressive accumulation of pyridine in the culture liquid and the cells were washed out. The maximum specific growth rate (mu max = 0.23 h-1) and the Ks value (0.22 mM) for growth on pyridine were determined from the residual pyridine concentrations measured within the range of stable steady states. With growth on the substrate mixture, the specific pyridine consumption rates and the residual pyridine concentrations were lower at similar dilution rates than with growth on pyridine alone, and stable steady states were established at dilution rates of up to 0.13 h-1. The maximum pyridine degradation rate was enhanced to 270 mg pyridine l-1 h-1 compared to 210 mg pyridine l-1 h-1 with growth on pyridine as a single substrate. An external nitrogen source did not need to be added in the case of growth on the substrate mixture. Fructose was assimilated by means of ammonium released from pyridine. Analysis of the nitrogen balance furnished proof that pyridine is an energy-deficient substrate; pyridine was assimilated and dissimilated at a ratio of 1 mol/0.67 mol respectively. The resulting yield coefficient was about 0.55 g dry weight/g pyridine. Moreover, it was demonstrated that, in regard to the biologically usable energy, 1 mol pyridine corresponds to 0.43 mol fructose.
Biodegradation, Environmental↗
Effect of pyridine on the expression of cytochrome P450 isozymes in primary rat hepatocyte culture.
In vivo administration of pyridine has been shown to increase the activity and content of several forms of cytochrome P450 by transcriptional and posttranscriptional mechanisms. The effect of pyridine on CYP1A and CYP2E1 isozymes was studied in a rat hepatocyte culture model. Hepatocytes were isolated from non-induced rats and seeded onto matrigel-coated dishes and incubated in William's medium E containing 10% fetal calf serum, hormones, and essential metals. Cultures were treated with 0, 10 or 25 mM pyridine for 1-3 days and microsomes were isolated to determine catalytic activity and for immunoblot analysis, and total RNA was isolated for mRNA determinations. CYP2E1 content, CYP2E 1 mRNA, and CYP2E1 catalyzed oxidation of p-nitrophenol declined during culture to values of 3, 30 and 19% that of initial, non-cultured controls by day 3 of culture. Pyridine prevented this decline of CYP2E1 protein and activity such that 60-80% original activity remained after 3 days of culture in the presence of 25 mM pyridine. However, pyridine did not prevent the fall in CYP2E1 mRNA levels, nor did pyridine increase the content or activity of CYP2E1 above initial values of microsomes from freshly isolated hepatocytes. Pyridine increased the content of CYP1A2 and the oxidation of ethoxyresorufin 2-4 fold compared to cultures incubated without pyridine over the 3 day culture period. CYP1A1 levels, which rapidly declined, were induced and maintained in the presence of pyridine. Pyridine increased CYP1A content and activity 2-3 fold over initial values of freshly isolated hepatocytes. These increases were associated with corresponding increases in CYP1A mRNA levels. CYP1A2, but not CYP1A1, mRNA levels increased in the cultures incubated in the absence of pyridine. These results indicate that pyridine has different effects on CYP1A and CYP2E1 in this hepatocyte culture model. Pyridine appears to modulate CYP2E1 levels by posttranscriptional mechanisms as CYP2E1 activity and content were maintained in the presence of pyridine under conditions in which CYP2E1 mRNA levels declined. These mechanisms may involve increased translational efficiency of existing CYP2E1 mRNA or stabilization of CYP2E1 protein against degradation. Pyridine increased CYP1A1 and CYP1A2 content, activity and mRNA levels, either inducing CYP1A transcription or stabilizing CYP1A mRNA. Hepatocyte cultures may be a useful model to study the interaction of pyridine with P450 isozymes and their associated drug-mediated toxicity.
Animals↗
Multinuclear magnetic resonance spectroscopy studies of the structuration of the tunnels of sepiolite in the presence of intracrystalline pyridine molecules.
Sepiolite, a naturally occurring magnesiosilicate nanoporous clay mineral with a tunnel structure, contains two types of water molecules in the structure: zeolitic water trapped inside the tunnels and structural water molecules which interact strongly with magnesium cations. The zeolitic water was removed by heating the sepiolite to 120 degrees C. The partially dehydrated sepiolite absorbed pyridine vapor to produce an intercalated material where the pyridine takes the place of the zeolitic water. 1H solid-state MAS NMR spectroscopy showed that there is isotopic H/D exchange between pyridine-d5 and the remaining structural water molecules of the sepiolite framework. The exchange takes place at room temperature over several days. Wide line solid state 2H NMR of the sequestered pyridine-d5 showed that two populations of pyridine molecules coexist in the material: one very mobile physisorbed population, which can be removed by heating at 90 degrees C, and a population due to pyridine trapped in the tunnels. Except for small in-plane librations, the trapped pyridine was shown to be held rigidly by the sepiolite. When the pyridine intercalated material is heated at 400 degrees C the structural water and some of the pyridine is lost. The remaining pyridine takes the place of the structural water to produce a new inorganic-organic nanohybrid material with the pyridine bound to the terminal Mg(II) in the structure. The pyridine in this material as well as the intercalated material was characterized by slow-spinning 15N and 13C CP/MAS NMR spectroscopy. The 15N NMR was shown to be a very sensitive probe to characterize the various types of pyridine. The data indicate that pyridine molecules in the inorganic-organic nanohybrid material are directly bound to magnesium cations exposed in the tunnels of sepiolite.
Journal Article↗
Enhanced hepatic expression of P450IIE1 following inhalation exposure to pyridine.
Previous research has shown that intraperitoneal injection of the solvent pyridine results in a dose- and time-dependent induction of hepatic P450IIE1 in rats, with a twofold increase observed at 6 hr post-treatment. However, inhalation is the primary route of exposure expected for humans exposed to pyridine in laboratory and industrial settings or in tobacco smoke. In view of the potency and rapidity of induction associated with pyridine treatment, research was initiated to examine whether inhalation of the solvent at the current threshold limit value level of 5 ppm or at an elevated level of 440 ppm resulted in sufficient nasal and pulmonary uptake and systemic redistribution to cause increased hepatic expression of rat cytochrome P450IIE1. Rats were exposed, 6 hr/day, to 5 ppm pyridine for 4 days; to 440 ppm pyridine for 1 or 4 days; or to filtered air for 1 or 4 days. Rats were sacrificed 18 hr after the last exposure. Liver samples were taken from the air- and pyridine-exposed rats. Expression of immunoreactive P450IIE1 was examined in tissue sections using immunohistochemistry and in microsomal preparations using Western blot analyses. Hepatic tissue obtained from rats exposed to 5 ppm pyridine for 4 days or to 440 ppm pyridine for 1 or 4 days displayed significantly elevated levels of immunoreactive P450IIE1. Immunohistochemical analyses of liver sections showed that inhalation of pyridine at 5 ppm resulted in an elevated expression of P450IIE1 in hepatocytes surrounding terminal hepatic venules (THVs). Exposure to 440 ppm pyridine caused both increased expression of IIE1 in hepatocytes surrounding THVs after a single 6-hr exposure and an approximately three- to fourfold increase in the total number of cells expressing IIE1 after 4 days of exposure. Dilution analysis of immunohistochemically stained tissue revealed a significant difference between air-exposed controls and pyridine-exposed rats, at all exposure levels. P450IIE1 levels in microsomes isolated from rats receiving 5 and 440 ppm pyridine for 4 days were increased 2.5- and 10-fold as judged from scanning laser densitometry. This study reveals that inhalation of pyridine vapors at levels equal to or greater than the current threshold limit value of 5 ppm results in significant hepatic induction of P450IIE1 in rats.
Administration, Inhalation↗
Influence of a supplementary carbon source on biodegradation of pyridine by freely suspended and immobilized Pimelobacter sp..
The effect of the presence of supplementary glucose or acetate on the growth and pyridine-degrading activity of freely suspended and calcium-alginate-immobilized Pimelobacter sp. was investigated. Although the supplementary carbon sources could be degraded simultaneously with pyridine, Pimelobacter sp. exhibited a preference for pyridine over supplementary carbon sources. Thus, the pyridine-degrading activity of the freely suspended cells was not decreased significantly by the addition of either glucose (1.5-6 mM) or acetate (6-24 mM) to the pyridine (6-24 mM). In the semi-continuous immobilized cell culture, immobilized cells also exhibited a preference for pyridine over supplementary carbon sources and did not switch their substrate preference throughout the culture. Owing to a high cell concentration, the volumetric pyridine degradation rate at 24 mM pyridine in the immobilized cell culture was approximately six times higher than that in the freely suspended cell culture. Furthermore, the immobilized cells could be reused 16 times without losing their pyridine-degrading activity during the culture period tested. Taken together, the use of immobilized Pimelobacter sp. for the degradation of pyridine is quite feasible because of the preference for pyridine over supplementary carbon sources, the high volumetric pyridine degradation rate, and the reusability of immobilized cells.
Acetates↗
Mutagenicity of structurally related phenylazo-3-pyridines in Salmonella typhimurium.
Studies were conducted to explore structure-activity relationships for 4'-N,N-dimethylamino-1'-phenylazo-3-pyridine and nine structurally related compounds in Salmonella typhimurium tester strains TA1535, TA100, TA1537, TA1538, TA98. Each compound was tested for mutagenicity at five or more concentrations that varied from 10-5000 micrograms/plate. We used the standard plate test and the investigations were carried out both in the absence and presence of Aroclor-1254-induced rat-liver homogenate and the components of the NADPH-generating system. Negative response was observed for 4'-N,N-dimethylamino-1'-phenylazo-3-pyridine and five of its analogues (4'-N,N-diethylamino-1' phenylazo-3-pyridine; 4'-N,N-di-(beta-hydroxyethylamino)-1' phenylazo-3-pyridine; 4'-N-methylamino sulfonic acid-1'-phenylazo-3-pyridine; 4'-N,N-dimethylamino-6'-acetamido-1' phenylazo-3-pyridine, and 4'-N,N-di-(beta-hydroxyethylamino)-6'-methyl-l' phenylazo-3-pyridine). When S9 induced by Aroclor-1254 was present, the compound 4'-N,N-dimethylamino-6-methoxy-1' phenylazo-3-pyridine exhibited mutagenic activity in the two strains TA1538 and TA98. The compound 4',6'-diamino-3-methyl-1'-phenylazo-3-pyridine was also mutagenic, both in the presence and in the absence of S9 mix. The two compounds 4'-N,N-dimethylamino-6-butoxy-1'-phenylazo-3-pyridine and 4'N,N-di-(beta-hydroxyethylamino)-1'-phenylazo-3-[6-N,N-di-(beta- hydroxyethylamino) pyridine were either weakly mutagenic or nonmutagenic. On the basis of these data, it is concluded that the mutagenicity of phenylazo-3-pyridines, like monocyclic aromatic amines and azo dyes, is influenced by the nature of the substituent chemical groups and their positions in the molecular structure of the compounds.
Animals↗
Comparative induction of CYP1A1 expression by pyridine and its metabolites.
We compared pyridine and five of its metabolites in terms of (i) in vivo induction of CYP1A1 expression in the lung, kidney, and liver in the rat and (ii) in vitro binding to, and activation of, the aryl hydrocarbon receptor (AhR) in cytosol from rat liver or Hepa1c1c7 cells. Following a single 2.5 mmol/kg ip dose of either pyridine, 2-hydroxpyridine, 3-hydroxypyridine, 4-hydroxypyridine, N-methylpyridinium, or pyridine N-oxide, CYP1A1 activity (ethoxyresorufin O-deethylase), protein level (as determined by Western blotting), and mRNA level (as determined by Northern blotting) were induced by pyridine, N-methylpyridinium, and pyridine N-oxide in the lung, kidney, and liver. The induction by N-methylpyridinium or pyridine N-oxide was comparable to or greater than that by pyridine in some tissues. 2-Hydroxypyridine and 3-hydroxypyridine caused tissue-specific induction or repression of CYP1A1, whereas 4-hydroxypyridine had no effect on the expression of the enzyme. Pyridine and its metabolites elicited weak activation of the aryl hydrocarbon receptor in a gel retardation assay in cytosol from rat liver but not Hepa 1c1c7 cells. However, the receptor activation did not parallel the in vivo CYP1A1 induction by the pyridine compounds, none of which inhibited binding of ¿(3)H2,3,7, 8-tetrachlorodibenzo-p-dioxin to AhR in a competitive assay in rat liver cytosol. The findings are consistent with a role of pyridine metabolites in CYP1A1 induction by pyridine but do not clearly identify the role of aryl hydrocarbon receptor in the induction mechanism.
Animals↗
Inhibition of alcohol dehydrogenase from yeast by pyridine.
1. Inhibition by pyridine of reduction of NAD by ethanol in the presence of yeast alcohol dehydrogenase was studied at 25 degrees in 60mm-glycine buffer (K(+), pH9.3). 2. The apparent Michaelis constant for ethanol increases linearly and that for NAD increases non-linearly with pyridine concentration. 3. Rates, v, observed in the presence of pyridine are lower than the values calculated from the effect of pyridine on the two apparent Michaelis constants and are described by the expression V/v={1+5.8[pyridine]}x{1+0.016(1+124 [pyridine)]/[EtOH]}x{1+0.00019(1+3.3[pyridine]+110 [pyridine](2))/[NAD]}. 4. Mixed inhibitor studies with pyridine and N(1)-methylnicotinamide chloride in 40mm-pyrophosphate buffer (Na(+), pH8.2) indicated little interaction of pyridine with the ;pyridinium site' of the dehydrogenase (interaction constant, alpha, 2.1). 5. The possible competition of ethanol and pyridine for a zinc atom in the active centre of yeast alcohol dehydrogenase is discussed.
Alcohol Oxidoreductases↗
New pyridine carboxamide ligands and their complexation to copper(II). X-Ray crystal structures of mono-, di, tri- and tetranuclear copper complexes.
Seven new pyridine dicarboxamide ligands H2L(1-7) have been synthesised from condensation reactions involving pyridine-2,6-dicarboxylic acid (H2dipic), pyridine-2,6-dicarbonyl dichloride or 2,6-diaminopyridine with heterocyclic amine or carboxylic acid precursors. Crystallographic analyses of N,N'-bis(2-pyridyl)pyridine-2,6-dicarboxamide monohydrate (H2L8 x H2O), N,N'-bis[2-(2-pyridyl)methyl]pyridine-2,6-dicarboxamide and N,N'-bis[2-(2-pyridyl)ethyl]pyridine-2,6-dicarboxamide monohydrate revealed extensive intramolecular hydrogen bonding interactions. 2,6-Bis(pyrazine-2-carboxamido)pyridine (H2L6) and 2,6-bis(pyridine-2-carboxamido)pyridine (H2L7) reacted with copper(II) acetate monohydrate to give tricopper(II) complexes [Cu3(L)2(mu2-OAc)2]. X-Ray crystallography confirmed deprotonation of the amidic nitrogen atoms and that the (L6,7)2- ligands and acetate anions hold three copper(II) ions in approximately linear fashion. H2L8. Reacted with copper(II) tetrakis(pyridine) perchlorate to give [Cu(L8)(OH2)]2 x 2H2O, in which (L8)2- was tridentate through the nitrogen atoms of the central pyridine ring and the deprotonated carboxamide groups at one copper centre, with one of the terminal pyridyl rings coordinating to the other copper atom in the dimer. The corresponding reaction using H2L7 gave [Cu3(L7)2(py)2][ClO4]2, which transformed during an attempted recrystallisation from ethanol under aerobic conditions to a tetracopper(II) complex [Cu4(L7)2(L7-O)2].
Journal Article↗
Potentiation of carbon tetrachloride-induced hepatotoxicity and pneumotoxicity by pyridine.
Induction of P450IIE1 by pyridine was compared with that by ethanol, and the resulting potentiation of the pneumotoxicity and hepatotoxicity following carbon tetrachloride inhalation by pyridine was examined. Rats were treated with ethanol as either a 10% solution in the drinking water or as a daily bolus (3 ml/kg, ip) dose for 7 days or one bolus dose of pyridine (200 mg/kg, ip) and compared for P450IIE1 apoprotein content by immunoblot analysis. Ethanol in the drinking water and pyridine elevated both hepatic and pulmonary P450IIE1 apoprotein content, but bolus dose ethanol did not. The induction was greatest in the pyridine group. In the interaction study, rats were treated with pyridine (200 mg/kg, ip) and 12 hours later were exposed to CCl4 (8000 ppm for 3 hours). Pulmonary injury and hepatic damage were assessed 24 hours later by bronchoalveolar lavage fluid (BALF) analysis [gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and total protein] and serum sorbitol dehydrogenase (SDH) activity, respectively. Pyridine alone had no effect on BALF or SDH but enhanced GGT and LDH release into the BALF and SDH release into the serum when compared with CCl4 exposure alone. Evaluation of the liver at the light microscopic level revealed characteristic CCl4-induced centrilobular necrosis which was potentiated by pyridine. No changes were observed in the lung by light microscopic evaluation. Pyridine induced pulmonary and hepatic microsomal apoprotein levels of cytochrome P450IIE1 two- and 2- to sixfold, respectively. Exposure to CCl4 decreased hepatic but not pulmonary P450IIE1 levels. Induction of cytochrome P450IIE1 by pyridine increases the bioactivation of CCl4 in both the liver and lung, leading to enhanced toxicity.
Administration, Inhalation↗
Toxicity and anaerobic biodegradability of pyridine and its derivatives under sulfidogenic conditions.
Attempts were made to correlate the chemical structure of pyridine and 15 pyridine derivatives with both their biodegradability by estuarine sediment microorganisms under anaerobic conditions and also with their toxicity to the marine bacterium Vibrio fischeri Beijerinck 1889 by using the Microtox bacterial assay. Among monosubstituted pyridines, comparisons of different substituents at positions C-2, C-3, or C-4 atom of the pyridine ring showed that isomers of carboxylpyridine (COOHPYR), hydroxypyridine (OHPYR), and cyanopyridine (CNPYR) were more susceptible to biotransformation than isomers of chloropyridine (ClPYR) and methylpyridine (CH3PYR) in anoxic estuarine sediment slurries under sulfidogenic conditions. Isomers with the functional group at the C-2 or C-3 atom of the pyridine ring were biotransformed faster than those with the same functional group at C-4. The only exception was 4-ClPYR, which was biotransformed within 130 days, while 2- and 3-ClPYR continued to persist in the anoxic sediment slurries. Median effect concentrations (EC50) of pyridine and pyridine derivatives were in the range of 0.027 to 49.1 mmol/L. Pyridine derivatives with -CN and -OH functional groups tended to be less toxic, while pyridine derivatives with -CH3, -Cl, and -COOH functional groups tended to be more toxic. Isomers with the substituent at C-2 were less toxic than the C-3 or C-4 isomers. There was no clear correlation between the pseudo-first-order rate constants for the microbial transformation of pyridine and its derivatives and their toxicity to the marine bacterium.
Anaerobiosis↗
Excretion of the N(2)-glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in urine and its relationship to CYP1A2 and NAT2 activity levels in humans.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic aromatic amine formed in meat products during cooking. The genotoxity of PhIP requires an initial cytochrome P450-mediated N-oxidation followed by N-O-esterification catalyzed generally by N-acetyltransferases and sulfotransferases. This study examined the urinary excretion of N(2)-(beta-1-glucos-iduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-the major human urinary N-oxidation metabolite of PhIP-and determined its relationship to individual activity levels of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). The subjects (33 males and 33 females) in the dietary study were phenotyped for their CYP1A2 and NAT2 activity prior to consumption of meat-based diet, and urine collections were obtained 0-12 and 12-24 h after ingestion of the meal. Acidic hydrolysis of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine and its d(3)-analog to form their respective deaminated products 2-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (2-OH-PhIP) was used in the assay. The products after derivatization were analyzed by capillary gas chromatography-negative ion chemical ionization mass spectrometry with selective ion monitoring. The amount of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine measured as the acid hydrolysis product 2-OH-PhIP in the 0-12 h urine was 20.2 +/- 8.0% (mean +/- SD) of the ingested dose; the median was 18.8% and the range varied from 5.4 to 39.6% within the group. In a subset (n = 18) of samples from individual urine collected from the 12-24 h period, an average value of 4.4 +/- 2.5% (+/- SD) of the dose was recovered. The excretion of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the 0-12 h urine was significantly related to the quantity of PhIP ingested for all subjects (r = 0.52, P <0.0001). Linear regression analysis of the relationship between the excretion level of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, adjusted for meat intake and CYP1A2 activity in the combined group of males and females showed a low association (r = 0.25, P = 0.05). There was no association between the amount of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimid-azo[4,5-b]pyridine in urine and NAT2 activity levels of the subjects nor with the age of the subjects. N(2)-(beta-1-glucosi-duronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine comprised a significant proportion of the ingested dose in some individuals; however, considerable variation was found within the group. The results indicate that interindividual differences in the rates of N-oxidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, as well as phase II glucuronidation reactions regulate the formation of this metabolite in humans.
Arylamine N-Acetyltransferase↗
Mesangial accumulation of GA-pyridine, a novel glycolaldehyde-derived AGE, in human renal disease.
BACKGROUND: Advanced glycation end products (AGEs) contribute to diabetic and atherosclerotic end-organ damage, but the mechanisms of AGE-formation and AGE-induced damage are unclear. Glycolaldehyde (GA) is a Maillard-reaction intermediate and can be formed by reaction of L-serine with the myeloperoxidase-system. GA reacts with proteins to form AGEs, such as GA-pyridine, which is specific for protein modification by GA. GA-pyridine accumulates in human atherosclerotic lesions. As atherosclerosis and progressive glomerulosclerosis share many similarities, we hypothesized that GA-pyridine accumulates in renal diseases, especially those with prominent mesangial involvement. METHODS: Paraffin-embedded renal biopsies from 55 patients with various renal diseases, as well as control tissue, obtained from the unaffected part of kidneys from 10 patients with renal cell carcinoma were immunohistochemically stained with a monoclonal antibody directed against GA-pyridine and were scored semiquantitatively. Additional sections were scored for mesangial matrix expansion (MME) and focal glomerular sclerosis (FGS). RESULTS: In normal human kidneys, GA-pyridine was mainly localized in tubular epithelial cells, but not in the glomerular mesangium. Significant mesangial GA-pyridine accumulation was found in disorders with mesangial involvement as a common denominator. In contrast, mesangial GA-pyridine accumulation was less prominent in renal diseases without prominent mesangial involvement. Moreover, mesangial GA-pyridine accumulation was more pronounced in kidneys with higher MME and FGS scores across the different diagnoses. CONCLUSION: GA-pyridine accumulates in the mesangium in human renal disease, in particular in disorders with mesangial involvement. Further studies should elucidate whether mesangial GA-pyridine plays a role in the progression of glomerular damage.
Acetaldehyde↗