N'-Nitrosonornicotine (NNN) and N-nitrosopiperidine (NPIP) are potent esophageal and nasal cavity carcinogens in rats and pulmonary carcinogens in mice. N-Nitrosopyrrolidine (NPYR) induces mainly liver tumors in rats and is a weak pulmonary carcinogen in mice. These nitrosamines may be causative agents in human cancer. alpha-Hydroxylation is believed to be the key activation pathway in their carcinogenesis. P450 2As are important enzymes of nitrosamine alpha-hydroxylation. Therefore, a structure-activity relationship study of rat P450 2A3, mouse P450 2A4 and 2A5, and human P450 2A6 and 2A13 was undertaken to compare the catalytic activities of these enzymes for alpha-hydroxylation of (R)-NNN, (S)-NNN, NPIP, and NPYR. Kinetic parameters differed significantly among the P450 2As although their amino acid sequence identities were 83% or greater. For NNN, alpha-hydroxylation can occur at the 2'- or 5'-carbon. P450 2As catalyzed 5'-hydroxylation of (R)- or (S)-NNN with Km values of 0.74-69 microM. All of the P450 2As except P450 2A6 catalyzed (R)-NNN 2'-hydroxylation with Km values of 0.73-66 microM. (S)-NNN 2'-hydroxylation was not observed. Although P450 2A4 and 2A5 differ by only 11 amino acids, they were the least and most efficient catalysts of NNN 5'-hydroxylation, respectively. The catalytic efficiencies (kcat/Km) for (R)-NNN differed by 170-fold whereas there was a 46-fold difference for (S)-NNN. In general, P450 2As catalyzed (R)- and (S)-NNN 5'-hydroxylation with significantly lower Km and higher kcat/Km values than NPIP or NPYR alpha-hydroxylation (p <0.05). Furthermore, P450 2As were better catalysts of NPIP alpha-hydroxylation than NPYR. P450 2A4, 2A5, 2A6, and 2A13 exhibited significantly lower Km and higher kcat/Km values for NPIP than NPYR alpha-hydroxylation (p <0.05), similar to previous reports with P450 2A3. Taken together, these data indicate that critical P450 2A residues determine the catalytic activities of NNN, NPIP, and NPYR alpha-hydroxylation.
N'-nitrosonornicotine (NNN) is a strong carcinogen. ... Determined NNN and its metabolites in rabbit blood by high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). ... Metabolic curves and pharmacokinetic parameters were obtained for NNN and its metabolites. ... The main metabolite of NNN was 4-hydroxy-4-(3-pyridyl)-butyric acid (hydroxy acid) and the major metabolic pathway was 5'-hydroxylation and subsequent secondary metabolite formation.
... When n'-nitrosonornicotine was incubated with liver microsomes from aroclor-pretreated rats, trace amt of 3'-hydroxy-n'-nitrosonornicotine and 4'-hydroxy-n'-nitrosonornicotine were produced and n'-nitrosonornicotine-1-n-oxide was a major metabolite. ...
Nasal septa in culture with their covering mucosa (from Sprague-Dawley rats) were exposed to 0.305 umol (5-(3)H)-N'-nitrosonornicotine. Incubations were carried out for 21 hr, and the DNA was isolated. The expt was repeated 3 times using 6 dishes containing 3 septa each. Hydrolysates of DNA isolated from cultured nasal mucosa contained radioactive peaks (pmol/mg DNA) eluting at 30 (0.5), 45 (0.2), 56 (0.4), 69 (0.3), and 82 (0.2) min. Only 45% of the radioactivity applied to the column was eluted. The peak eluting at 56 min was identified as 4-hydroxy-1-(3-pyridyl)-1-butanone.
Classification of carcinogenicity: 1) No adequate data are available in humans; 2) evidence in animals: Sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/
IARC Monographs:Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)
Volume 89: (2007) Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines
Volume 100E: (2012) Personal Habits and Indoor Combustions
来源:International Agency for Research on Cancer (IARC)
Male C57BL/6J mice were given iv injections of 7 mg (about 4 mu Ci) of N'-[pyrrolidine-2-(14)C] nitrosonornicotine per kg and frozen by immersion in dry ice:hexane at 0.1, 0.33, 1, 3, 9, and 24 hr after injection. ... At 6 min after administration, radioactivity was highest in liver, kidney, parotid gland, nasal epithelium, melanin, and contents of lower stomach; there was very little radioactivity at this time interval in bronchial epithelium. At later time intervals, there was increasing radioactivity in bronchial and nasal epithelium and sublingual and submandibular duct epithelium. By 24 hr after administration, virtually the only radioactivity remaining in the entire body was in the epithelium of the nasal cavity, bronchi, esophagus, and salivary glands and also in melanin, liver, proximal tubules of the kidney, and preputial gland. ...
2 Male F344 rats were given daily ip injections of (5-(3)H)-N'-nitrosonornicotine (0.407 umol, 1.11 mCi) for 3 days. Rats were sacrificed 24 hr after the last injection and DNA was isolated. DNA binding was observed as follows (pmol/mg of DNA): liver (0.54); lung (0.05); nasal mucosa (0.02); kidney and esophagus (< 0.005). HPLC analysis of enzymatic DNA hydrolysates obtained from rat livers gave chromatograms that had 2 peaks, one eluting from 40 to 50 min (0.2 pmol/mg DNA) and the other at 56 min (0.05 pmol/mg DNA). Only 48% of the radioactivity applied to the column eluted from the column. The peak eluting at 56 min was identified as 4-hydroxy-1-(3-pyridyl)-1-butanone.
Single intravenous doses of 4-5 mg/kg bw 2'-(14)C NNN were distributed in tissues of Fischer 344 or Sprague-Dawley rats within 5 min of injection. A high uptake of radioactivity was seen in the mucosa of the ethmo-, naso- and maxilloturbinates, in the submaxillary salivary glands, lachrymal glands, Zymbal glands, tarsal glands of the eyelids, preputial glands, esophagus and tongue, and in the contents of the stomach. After 24 hr, non-extractable radioactivity was present in the nasal, tracheobronchial and esophageal mucosa, and in the liver.
Male Fischer 344 rats that received a subcutaneous injection of 3-300 mg/kg body weight 2'-(14)C-NNN excreted 73-91% of the dose in urine over 48 hours. Less than 1% of the dose was detected in expired air. Male Syrian golden hamsters that were given subcutaneous injections of 60 mg/kg body weight 2'-(14)C-NNN excreted 62-78% of the dose in urine over 48 hours, 10% in feces and < 0.5% in expired air as (14)CO2. Urine was also the major pathway of excretion in male A/J mice after intraperitoneal injection of 50 mg/kg body weight (2'-(14)C-NNN.
Section 1. Chemical Product and Company Identification N'-Nitrosonornicotine Common Name/ Trade Name N'-Nitrosonornicotine Section 3. Hazards Identification Potential Acute Health Effects Hazardous in case of ingestion. Slightly hazardous in case of skin contact (irritant), of eye contact (irritant), of inhalation. Potential Chronic Health CARCINOGENIC EFFECTS: Classified 2B (Possible for human.) by IARC. Effects MUTAGENIC EFFECTS: Mutagenic for mammalian somatic cells. Mutagenic for bacteria and/or yeast. TERATOGENIC EFFECTS: Not available. DEVELOPMENTAL TOXICITY: Not available. Repeated or prolonged exposure is not known to aggravate medical condition. Section 4. First Aid Measures Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Get medical attention if irritation occurs. Skin Contact Wash with soap and water. Cover the irritated skin with an emollient. Get medical attention if irritation develops. Serious Skin Contact Not available. Inhalation If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Serious Inhalation Not available. Ingestion Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, call a physician immediately. Loosen tight clothing such as a collar, tie, belt or waistband. Serious Ingestion Not available. Section 5. Fire and Explosion Data Flammability of the Product May be combustible at high temperature. Auto-Ignition Temperature Not available. Flash Points Not available. Flammable Limits Not available. These products are carbon oxides (CO, CO2), nitrogen oxides (NO, NO2...). Products of Combustion Fire Hazards in Presence of Slightly flammable to flammable in presence of heat. Various Substances Explosion Hazards in Presence Risks of explosion of the product in presence of mechanical impact: Not available. of Various Substances Risks of explosion of the product in presence of static discharge: Not available. Fire Fighting Media SMALL FIRE: Use DRY chemical powder. and Instructions LARGE FIRE: Use water spray, fog or foam. Do not use water jet. Special Remarks on Not available. Fire Hazards Special Remarks on Explosion Not available. Hazards N'-Nitrosonornicotine Section 6. Accidental Release Measures Small Spill Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and dispose of according to local and regional authority requirements. Large Spill Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and allow to evacuate through the sanitary system. Section 7. Handling and Storage Precautions Keep away from heat. Keep away from sources of ignition. Ground all equipment containing material. Do not breathe dust. Wear suitable protective clothing. If you feel unwell, seek medical attention and show the label when possible. Keep away from incompatibles such as oxidizing agents. Storage Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above 0°C (32°F). Freeze. Section 8. Exposure Controls/Personal Protection Engineering Controls Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants below the exposure limit. Personal Protection Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves. Personal Protection in Case of Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used a Large Spill to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist BEFORE handling this product. Exposure Limits Not available. Section 9. Physical and Chemical Properties Physical state and appearance Solid. Odor Not available. Not available. Taste Molecular Weight 177.2 g/mole Yellow. (Light.) Color pH (1% soln/water) Not available. Boiling Point Not available. Melting Point 43°C (109.4°F) - 45 C. Critical Temperature Not available. Specific Gravity Not available. Not applicable. Vapor Pressure Vapor Density Not available. Not available. Volatility Odor Threshold Not available. Water/Oil Dist. Coeff. Not available. Ionicity (in Water) Not available. Dispersion Properties Not available. Solubility Not available. N'-Nitrosonornicotine Section 10. Stability and Reactivity Data The product is stable. Stability Instability Temperature Not available. Excess heat, incompatible materials Conditions of Instability Reactive with oxidizing agents. Incompatibility with various substances Corrosivity Not available. Special Remarks on Not available. Reactivity Special Remarks on Not available. Corrosivity Polymerization Will not occur. Section 11. Toxicological Information Routes of Entry Inhalation. Ingestion. Toxicity to Animals LD50: Not available. LC50: Not available. Chronic Effects on Humans CARCINOGENIC EFFECTS: Classified 2B (Possible for human.) by IARC. MUTAGENIC EFFECTS: Mutagenic for mammalian somatic cells. Mutagenic for bacteria and/or yeast. Other Toxic Effects on Hazardous in case of ingestion. Humans Slightly hazardous in case of skin contact (irritant), of inhalation. Special Remarks on Not available. Toxicity to Animals Special Remarks on May cause cancer. Chronic Effects on Humans May affect genetic material (mutagenic). Special Remarks on other Acute Potential Health Effects: Toxic Effects on Humans Skin: Causes skin irritation. Eyes: Causes eye irritation. Inhalation: Can cause respiratory tract irritation. Ingestion: No acute health effects are known at this time. Chronic Potential Health Effects: Ingestion: Repeated or prolonged ingestion may cause cancer. It may affect the liver. Section 12. Ecological Information Ecotoxicity Not available. Not available. BOD5 and COD Possibly hazardous short term degradation products are not likely. However, long term degradation products may Products of Biodegradation arise. Toxicity of the Products The product itself and its products of degradation are not toxic. of Biodegradation Special Remarks on the Not available. Products of Biodegradation N'-Nitrosonornicotine Section 13. Disposal Considerations Waste Disposal Waste must be disposed of in accordance with federal, state and local environmental control regulations. Section 14. Transport Information DOT Classification Not a DOT controlled material (United States). Not applicable. Identification Not applicable. Special Provisions for Transport DOT (Pictograms) Section 15. Other Regulatory Information and Pictograms California prop. 65: This product contains the following ingredients for which the State of California has found to Federal and State cause cancer, birth defects or other reproductive harm, which would require a warning under the statute: Regulations N'-Nitrosonornicotine California prop. 65 (no significant risk level): N'-Nitrosonornicotine: 0.0005 mg/day (value) California prop. 65: This product contains the following ingredients for which the State of California has found to cause cancer which would require a warning under the statute: N'-Nitrosonornicotine Illinois toxic substances disclosure to employee act: N'-Nitrosonornicotine Pennsylvania RTK: N'-Nitrosonornicotine Minnesota: N'-Nitrosonornicotine Massachusetts RTK: N'-Nitrosonornicotine New Jersey: N'-Nitrosonornicotine New Jersey spill list: N'-Nitrosonornicotine California Director's List of Hazardous Substances: N'-Nitrosonornicotine SARA 313 toxic chemical notification and release reporting: N'-Nitrosonornicotine California California prop. 65: This product contains the following ingredients for which the State of California has found Proposition 65 to cause cancer which would require a warning under the statute: N'-Nitrosonornicotine Warnings Other Regulations Not available. WHMIS (Canada) CLASS D-2A: Material causing other toxic effects (VERY TOXIC). Other Classifications DSCL (EEC) R40- Limited evidence of a S36/37- Wear suitable protective clothing and carcinogenic effect. gloves. Health Hazard HMIS (U.S.A.) 2 National Fire Protection 1 Flammability 1 Association (U.S.A.) Fire Hazard 2 0 Reactivity Health Reactivity 0 Specific hazard Personal Protection E WHMIS (Canada) (Pictograms) N'-Nitrosonornicotine DSCL (Europe) (Pictograms) TDG (Canada) (Pictograms) ADR (Europe) (Pictograms) Protective Equipment Gloves. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Wear appropriate respirator when ventilation is inadequate.
The interaction of a cobalt porphyrin with cancer-associated nitrosamines
摘要：
A cobalt porphyrin (CY-B) was presented, and its interaction with tobacco-specific nitrosamines (TSNAs) was investigated by UV-Vis spectroscopy and high-resolution mass spectrometry. The results revealed that the stoichiometry of the host-guest interaction was 1:2 and that the binding constant between CY-B and TSNAs was within the range of 0.78×10(8)-7.83×10(8)M(-2). The coordination strength between CY-B and TSNAs decreased in the sequence of NNN>NAB>NAT>NNK based on the binding constant. The interaction mechanism of CY-B with TSNAs involved a coordination interaction, and the π-π interaction between the porphyrin macrocycle and the aromatic frame of the TSNAs pyridines may also have been a driving force. The measured thermodynamic properties demonstrated that the reaction of CY-B with TSNAs was spontaneous and that the driving force for the interaction was a change in enthalpy. The reaction was exothermic, and an increasing temperature inhibited the interaction. The IR spectrum of the complex revealed that the NNO group of TSNAs and the metal cobalt of CY-B formed the six-coordinate complex.
Allomorph of isomer Z hydrochloride of alkylaminofurane derivative
申请人：——
公开号：US20040048922A1
公开（公告）日：2004-03-11
Allomorph of Z isomer of N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-
1,1
-ethenediamine hydrochloride, with two carbon atoms linked by a rigid ethylenic bond, marked by an asterisk (*), characterized by the following structural formula:
1
wherein -Fur- represents a furane ring.
[EN] MOLECULARLY IMPRINTED POLYMERS SELECTIVE FOR NITROSAMINES AND METHODS OF USING THE SAME<br/>[FR] POLYMERES A EMPREINTES MOLECULAIRES SELECTIFS DES NITROSAMINES ET PROCEDES D'UTILISATION DESDITS POLYMERES
申请人：MIP TECHNOLOGIES AB
公开号：WO2005112670A1
公开（公告）日：2005-12-01
A class of molecularly imprinted polymers that specifically recognizes and binds to nitrosamines members of which class are useful, for example, in analysis and separation of nitrosamines from biological fluids. Such molecularly imprinted polymers are also useful in methods of treating and manufacturing tobacco products and materials.
TOBACCO/CATALYST MIXTURES FOR REDUCING TOXIC COMPOUNDS IN TOBACCO SMOKE
申请人：UNIVERSIDAD DE ALICANTE
公开号：EP2092838A1
公开（公告）日：2009-08-26
Tobacco-catalyst mixtures for reducing the toxic compounds present in tobacco smoke.
The use of certain additives to be mixed in with tobacco to reduce the quantity of toxic and cancerous substances present in tobacco smoke. The composition of tobacco-additive as well as preparation procedures is also an objective of this invention.
Methods of selectively reducing constituents in tobacco as well as the tobacco obtained by such methods are disclosed. Subcritical fluids, e.g., liquid carbon dioxide, serve as the reduction media.
Tabacco plants having reduced nicotine demethylase activity
申请人：U.S. Smokeless Tobacco Company
公开号：EP2333081A2
公开（公告）日：2011-06-15
The present invention generally relates to methods and materials involved in producing tobacco plants having reduced levels of conversion of nicotine to nornicotine. In certain embodiments, the invention is directed to mutations in a nicotine demethylase gene, tobacco plants comprising mutations in a nicotine demethylase gene, and tobacco compositions and products thereof. In other embodiments, the invention is directed toward nicotine demethylase RNA interference, tobacco plants comprising a nicotine demethylase RNA interference transgene, and tobacco compositions and products thereof.
