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PubMed2002

Inhibitory effects of cinnamaldehyde on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung carcinogenesis in rasH2 mice.

Previously we reported a lack of modification by cinnamaldehyde (CNMA) of development of lung proliferative lesions induced by urethane in CB6F1-TgHras2 (rasH2) mice. In the present study, we re-evaluated CNMA effects using the same rasH2 strain and non-transgenic littermates initiated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Sixteen mice/strain/sex received intraperitoneal NNK injections at a dose of 3 mg/mouse once a week for 2 weeks followed by free feeding of commercial diet containing 5000 ppm CNMA for 26 weeks. Additional groups were maintained without NNK injection and/or CNMA feeding for 28 weeks. Lung tumors were induced by NNK in both rasH2 and non-Tg males and females at incidence ranging from 63 to 100%. CNMA treatment significantly reduced the combined incidence of adenomas and carcinomas from 86 to 31% in rasH2 males (P<0.05), but no significant influence was evident in females. The multiplicity of NNK-induced lung tumors was also significantly reduced in rasH2 males given CNMA (P<0.01). Similar effects were also observed in non-Tg females given CNMA after NNK initiation. The results of our study strongly indicate that CNMA is capable of inhibiting development of NNK-initiated pulmonary tumorigenesis in rasH2 and non-Tg mice.

Animals↗
PubMed2001

Inhibitory effect of mandarin juice rich in beta-cryptoxanthin and hesperidin on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary tumorigenesis in mice.

Previously we reported that a commercial Satsuma mandarin (Citrus unshiu Marc.) juice (MJ), MJ2 and MJ5, especially MJ5, effectively suppressed chemically-induced rat colon carcinogenesis (Int. J. Cancer 88 (2000) 146). MJ2 and MJ5 prepared from MJ have higher amounts of beta-cryptoxanthin and hesperidin than MJ, suggesting that principle chemopreventive factors in MJs may be beta-cryptoxanthin and hesperidin. Present study was conducted to test whether these MJs could modify carcinogenesis in other organ, lung initiated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male A/J mice. Mice were given an intraperitoneal injection of NNK (10 micromol in saline/mouse) to induce pulmonary neoplasms. They also received MJ, MJ2 or MJ5 as a drinking water at night for 21 weeks, starting 1 week after the NNK injection. Treatments with MJ, MJ2, and MJ5 reduced the incidence of lung tumors and the inhibition by MJ5 (29% reduction) was statistically significant (P<0.05). MJs treatment lowered the multiplicity of lung neoplasms without statistical significance. Immunohistochemically, MJs, especially MJ5, reduced proliferating cell nuclear antigen (PCNA)-positive index in the lung tumors without affecting PCNA index in hyperplastic alveolar cell lesions. These findings might suggest that MJ5, which contain 3.9 mg beta-cryptoxanthin and 100 mg hesperidin in 100 g sample), has chemopreventive ability against NNK-induced mouse lung tumorigenesis.

Animals↗
PubMed2003

Inhibitory effects of propolis granular A P C on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice.

We examined the effect of propolis granular A. P. C on lung tumorigenesis in female A/J mice. Lung tumors were induced by the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administered in drinking water for 7 weeks in mice maintained on an AIN-76A semi-synthetic diet. Propolis granular A. P. C (100 mg/kg body wt.) was administered orally daily for 6 days/week from 1 week before NNK administration and throughout the experiment. Sixteen weeks after the NNK treatment, the mice were killed and the number of surface lung tumors was measured. The number of lung tumors in mice treated with NNK alone for 7 weeks (9.4 mg/mouse) was significantly more than in that observed in control mice. Propolis granular A. P. C significantly decreased the number of lung tumors induced by NNK. These results indicate that propolis granular A. P. C is effective in suppressing NNK-induced lung tumorigenesis in mice.

Administration, Oral↗
PubMed1997

A study of tobacco carcinogenesis, LIII: carcinogenicity of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustela vison).

In an earlier study, young male and female mink (Mustela vison) were found to be highly susceptible to the carcinogenic effect of N'-nitrosonornicotine (NNN). In this follow-up study we tested (i) the importance of the age of the animals with regard to the carcinogenic effect of NNN, (ii) the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and (iii) the combined carcinogenic effect of NNN plus NNK. (I) In the previous study, the latency of nasal tumor induction by NNN (11.9 mM) averaged 84 +/- 40 weeks upon twice weekly applications, starting at the age of 3 weeks and continuing for 38 weeks. In this bioassay, giving NNN in 28 weeks but starting at the age of 3 months, it took, on the average, 97 +/- 29 weeks to induce malignant nasal tumors, primarily esthesioneuroepithelioma with invasion of the brain. (ii) NNK (6.3 mM), given by s.c. injection, induced nasal carcinoma with invasion of the forebrain after 77 +/- 39 weeks. (iii) NNN (11.9 mM) plus NNK (6.3 mM) led to the same type of carcinoma but at an accelerated pace, namely after 71 +/- 57 weeks. This study supports the earlier observation that tobacco-specific N-nitrosamines induce malignant tumors of the nasal cavity with invasion of the brain, dependent to some degree on the age of the mink at first application. NNK appears to be a stronger carcinogen than NNN in mink which follows the observations made with mice, rats and hamsters. It is suggested that combined administration of NNN with NNK induces a stronger carcinogenic effect than NNN or NNK given alone.

Age Factors↗
PubMed1997

Oxidative DNA damage in tissues of pregnant female mice and fetuses caused by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces the promutagenic oxidative-damage DNA lesion, 8-oxo-2'-deoxyguanosine (8-oxo-dG), in adult animals. To investigate whether this alteration occurs in DNA after transplacental exposure, pregnant Swiss mice were administered single or multiple doses of NNK. The 8-oxo-dG was quantified in placenta, and maternal and fetal tissues. In maternal lungs, single and multiple doses of NNK significantly increased levels of 8-oxo-dG by 23% and 32%, respectively. In maternal liver, a significant 38% increase was observed after multiple dose treatment. In the fetuses, a significant 45% increase in 8-oxo-dG levels was observed in liver after multiple doses of NNK. This is the first demonstration of oxidative DNA damage after transplacental exposure to NNK, and supports the concept of maternal smoking as a contributor to the development of childhood cancer.

Animals↗
PubMed1998

The inhibitory effect of vitamin E on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in mice based on the regulation of polyamine metabolism.

The present study was carried out in order to estimate a usefulness of vitamin E against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Feeding high doses of vitamin E suppressed the NNK-induced elevation of the activity of ornithine decarboxylase, a key enzyme of polyamine biosynthesis, in the lungs of mice at 4 weeks after injection. In contrast, the vitamin elevated the NNK-induced decrease of the activity of spermidine/spermine N1-acetyltransferase, a key enzyme of polyamine biodegradation. In conjugation with these events, the NNK-increased level of proliferating nuclear cell antigen as a marker of cell proliferation was suppressed by vitamin E treatment. Also, the supply of high doses of vitamin E suppressed NNK-induced lung tumorigenesis in mice. These results suggest that vitamin E inhibits the development of lung tumors in mice treated with NNK, partly due to the regulation of polyamine metabolism.

Animals↗
PubMed1999

Effects of protocatechuic acid, S-methylmethanethiosulfonate or 5-hydroxy-4-(2-phenyl-(E)ethenyl)-2(5H)-furanone(KYN-54) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary carcinogenesis in mice.

Modifying effects of dietary exposure of protocatechuic acid (PCA), a natural monophenolic compound, S-methylmethanethiosulfonate (MMTS), an organosulfur compound newly isolated from cauliflower, and 5-hydroxy-4-(2-phenyl-(E)ethenyl)-2(5H)-furanone (KYN-54), a novel retinoidal butenolide compound, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (10 micromol, [corrected] single i.p. injection)-induced pulmonary carcinogenesis were examined in female A/J mice. Each of the test chemicals was given in diets during initiation or post-initiation phases (PCA, 1000 ppm; MMTS, 100 ppm; KYN-54, 200 ppm). All of these which had been proved to be chemopreventive mainly in digestive-organs carcinogenesis did not exert any preventive effect in this model when the incidence or multiplicity of pulmonary tumors (adenomas) of mice given NNK and the test chemical at the termination of the experiment (4 months) was compared to that of mice exposed to the carcinogen alone. In contrast, the multiplicity of lung tumors of mice receiving KYN-54 during the post-initiation phase was significantly larger than of the animals with NNK alone (P < 0.05), showing that KYN-54 has a promoting effect on pulmonary carcinogenesis in mice. These data indicate an organotropic activity of these compounds and suggest that candidate compounds for cancer chemoprevention need to be carefully examined for effectiveness in multiple organs by different models.

4-Butyrolactone↗
PubMed1999

Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice.

The potential activities of butylated hydroxyanisole (BHA), myo-inositol, curcumin, esculetin, resveratrol and lycopene-enriched tomato oleoresin (LTO) as chemopreventive agents against lung tumor induction in A/J mice by the tobacco smoke carcinogens benzo[a]pyrene (BaP) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were evaluated. Groups of 20 A/J mice were treated weekly by gavage with a mixture of BaP and NNK (3 micromol each) for 8 weeks, then sacrificed 26 weeks after the first carcinogen treatment. Mice treated with BHA (20 or 40 micromol) by gavage 2 h before each dose of BaP and NNK had significantly reduced lung tumor multiplicity. Treatment with BHA (20 or 40 micromol) by gavage weekly or with dietary BHA (2000 ppm), curcumin (2000 ppm) or resveratrol (500 ppm) from 1 week after carcinogen treatment until termination had no effect on lung tumor multiplicity. Treatment with dietary myo-inositol (30,000 ppm) or esculetin (2000 ppm) from 1 week after carcinogen treatment until termination significantly reduced lung tumor multiplicity, with the effect of myo-inositol being significantly greater than that of esculetin. Treatment with dietary LTO (167, 1667 or 8333 ppm) from 1 week before carcinogen treatment until termination had no effect on lung tumor multiplicity. The results of this study demonstrate that BHA is an effective inhibitor of BaP plus NNK-induced lung tumorigenesis in A/J mice when administered during the period of carcinogen treatment and that, among the compounds tested, myo-inositol is most effective after carcinogen treatment.

Animals↗
PubMed2000

Carbonyl reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytosolic enzymes in human liver and lung.

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen, independent of the route and type of administration. There are competing metabolic activation and detoxification pathways. NNK is activated by alpha-hydroxylation at either the methyl or methylene carbonyl adjacent to the N-nitroso group to yield intermediates that methylate and pyridyloxobutylate DNA. Detoxification of NNK in humans usually occurs via carbonyl reduction to its hydroxy product NNAL, which undergoes glucuronosylation and final excretion. In vitro studies on NNK metabolism have usually been performed with tissue homogenates, microsomal fractions and/or purified microsomal enzymes, but cytosolic metabolism of NNK has been ignored until today. The results of this study demonstrate that cytosolic fractions of human liver and lung also participate in NNK metabolism. We provide evidence that a substantial degree of NNK carbonyl reduction occurs by cytosolic enzymes and that these enzymes may contribute to NNK detoxification in human liver and lung. The relative contribution of cytosolic vs. microsomal NNK carbonyl reduction is nearly identical in liver, whereas it is more than 3-fold higher in lung microsomes compared to lung cytosol. The inhibition profile suggested that mainly carbonyl reductase (EC 1.1.1.184) was active in cytosol of both organs. The expression of carbonyl reductase mRNA in liver and lung was proven by reverse transcription-(RT)-PCR. In conclusion, the results of this study provide the first data on cytosolic enzymes participating in NNK detoxification in human liver and lung.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2000

Effects of phenethyl isothiocyanate and benzyl isothiocyanate, individually and in combination, on lung tumorigenesis induced in A/J mice by benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Phenethyl isothiocyanate (PEITC) is an effective inhibitor of lung tumorigenesis induced in rats and mice by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while benzyl isothiocyanate (BITC) inhibits lung tumorigenesis induced in mice by another tobacco smoke carcinogen, benzo[a]pyrene (BaP). However, little is known about the inhibitory effects of PEITC and BITC in combination, or about the effects of PEITC or BITC on tumorigenesis by a mixture of NNK and BaP. In this study, we carried out a series of experiments pertinent to these questions. In Experiment 1, treatment of A/J mice with PEITC (6 micromol), BITC (6 micromol), or a combination of the two (6 micromol each) by gavage, 2 h prior to each of eight weekly gavage treatments with a mixture of BaP and NNK (3 micromol of each), had no effect on lung tumor multiplicity. In Experiment 2, we evaluated the inhibitory potential of four different mixtures of PEITC and BITC, administered by gavage 2 h prior to each of eight weekly doses of BaP and NNK, as given in Experiment 1. Mixtures of PEITC and BITC (12 micromol of each, or 12 micromol PEITC and 9 micromol BITC) significantly reduced lung tumorigenesis induced by a mixture of BaP and NNK. In Experiment 3, we investigated the effects of dietary PEITC (3 micromol/g diet), BITC (1 micromol/g diet), or a mixture of PEITC (3 micromol/g diet) and BITC (1 micromol/g diet). These compounds were started 1 week before, and continued through to 1 week after the eight weekly treatments with BaP and NNK. PEITC, and PEITC plus BITC, both significantly inhibited lung tumor multiplicity; inhibition was due mainly to PEITC. In Experiment 4, we tested dietary PEITC (3, 1, or 0.3 micromol/g diet) as an inhibitor of lung tumorigenesis induced by BaP, NNK, or BaP plus NNK using a protocol identical to that in Experiment 3. PEITC was an effective inhibitor of lung tumor multiplicity induced by NNK and a mixture of BaP plus NNK, but not by BaP. Dietary PEITC, or PEITC plus BITC, was more effective in these experiments than the compounds given by gavage. The results of this study demonstrate that proper doses of dietary PEITC and dietary as well as gavaged PEITC plus BITC are effective inhibitors of lung tumorigenesis induced in A/J mice by a mixture of BaP and NNK.

Analysis of Variance↗
PubMed1999

Modulation of reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by vitamin C-palmitate.

An in vitro study of effects of vitamin C-palmitate on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rat microsomes was performed. A sensitive assay method has been developed for the detection of metabolites of NNK in microsomes. Only the reduced metabolite of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL), was detected and measured in a time-course study. Vitamin C-palmitate enhanced the reduction of NNK in a concentration-dependent manner. The results indicate a significant increase in Vmax and K(m) in the presence of vitamin C. However, the rate of formation of NNAL at low substrate concentration varied. The ratio of Vmax to K(m) decreases. The results suggest that the kinetics are accounted for best by an uncompetitive activator binding model at low concentration of vitamin C. The uncompetitive binding model becomes sketchy at higher concentration of vitamin C. These observations infer that vitamin C loosely binds to the substrate-enzyme complex. Furthermore, the nature of the binding would facilitate the modulation of NNK biotransformation leading to the formation of NNAL. The results also show that vitamin C-palmitate is a potent activator of NNK reduction in rat liver microsomes. Thus, vitamin C-palmitate would mediate the metabolism of NNK through reduction. The resulting NNAL-glucuronide is more readily eliminated in urine.

Animals↗
PubMed2002

Structural definition of the active site and catalytic mechanism of 3,4-dihydroxy-2-butanone-4-phosphate synthase.

X-ray crystal structures of L-3,4-dihydroxy-2-butanone-4-phosphate synthase from Magnaporthe grisea are reported for the E-SO(4)(2-), E-SO(4)(2-)-Mg(2+), E-SO(4)(2)(-)-Mn(2+), E-SO(4)(2)(-)-Mn(2+)-glycerol, and E-SO(4)(2)(-)-Zn(2+) complexes with resolutions that extend to 1.55, 0.98, 1.60, 1.16, and 1.00 A, respectively. Active-site residues of the homodimer are fully defined. The structures were used to model the substrate ribulose 5-phosphate in the active site with the phosphate group anchored at the sulfate site and the placement of the ribulose group guided by the glycerol site. The model includes two Mg(2+) cations that bind to the oxygen substituents of the C2, C3, C4, and phosphate groups of the substrate, the side chains of Glu37 and His153, and water molecules. The position of the metal cofactors and the substrate's phosphate group are further stabilized by an extensive hydrogen-bond and salt-bridge network. On the basis of their proximity to the substrate's reaction participants, the imidazole of an Asp99-His136 dyad from one subunit, the side chains of the Asp41, Cys66, and Glu174 residues from the other subunit, and Mg(2+)-activated water molecules are proposed to serve specific roles in the catalytic cycle as general acid-base functionalities. The model suggests that during the 1,2-shift step of the reaction, the substrate's C3 and C4 hydroxyl groups are cis to each other. A cis transition state is calculated to have an activation barrier that is 2 kcal/mol greater than that of the trans transition state in the absence of the enzyme.

Catalytic Domain↗
PubMed2004

Endogenous 5-methylcytosine protects neighboring guanines from N7 and O6-methylation and O6-pyridyloxobutylation by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

All CG dinucleotides along exons 5-8 of the p53 tumor suppressor gene contain endogenous 5-methylcytosine (MeC). These same sites (e.g., codons 157, 158, 245, 248, and 273) are mutational hot spots in smoking-induced lung cancer. Several groups used the UvrABC endonuclease incision assay to demonstrate that methylated CG dinucleotides of the p53 gene are the preferred binding sites for the diol epoxides of bay region polycyclic aromatic hydrocarbons (PAH). In contrast, effects of endogenous cytosine methylation on the distribution of DNA lesions induced by tobacco-specific nitrosamines, e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have not been elucidated. In the work presented here, a stable isotope labeling HPLC-ESI-MS/MS approach was employed to analyze the reactivity of the N7 and O6 positions of guanines within hemimethylated and fully methylated CG dinucleotides toward NNK-derived methylating and pyridyloxobutylating species. 15N3-labeled guanine bases were placed within synthetic DNA sequences representing endogenously methylated p53 codons 154, 157, and 248, followed by treatment with acetylated precursors to NNK diazohydroxides. HPLC-ESI-MS/MS analysis was used to determine the relative yields of N7- and O6-guanine adducts at the 15N3-labeled position. In all cases, the presence of MeC inhibited the formation of N7-methylguanine, O6-methylguanine, and O6-pyridyloxobutylguanine at a neighboring G, with the greatest decrease observed in fully methylated dinucleotides and at guanines preceded by MeC. Furthermore, the O6-Me-dG/N7-Me-G molar ratios were decreased in the presence of the 5'-neighboring MeC, suggesting that the observed decline in O6-alkylguanine adduct yields is, at least partially, a result of an altered reactivity pattern in methylated CG dinucleotides. These results indicate that, unlike N2-guanine adducts of PAH diol epoxides, NNK-induced N7- and O6-alkylguanine adducts are not preferentially formed at the endogenously methylated CG sites within the p53 tumor suppressor gene.

5-Methylcytosine↗
PubMed2005

Stable isotope labeling-mass spectrometry analysis of methyl- and pyridyloxobutyl-guanine adducts of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in p53-derived DNA sequences.

The p53 tumor suppressor gene is a primary target in smoking-induced lung cancer. Interestingly, p53 mutations observed in lung tumors of smokers are concentrated at guanine bases within endogenously methylated (Me)CG dinucleotides, e.g., codons 157, 158, 245, 248, and 273 ((Me)C = 5-methylcytosine). One possible mechanism for the increased mutagenesis at these sites involves targeted binding of metabolically activated tobacco carcinogens to (Me)CG sequences. In the present work, a stable isotope labeling HPLC-ESI(+)-MS/MS approach was employed to analyze the formation of guanine lesions induced by the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) within DNA duplexes representing p53 mutational "hot spots" and surrounding sequences. Synthetic DNA duplexes containing p53 codons 153-159, 243-250, and 269-275 were prepared, where (Me)C was incorporated at all physiologically methylated CG sites. In each duplex, one of the guanine bases was replaced with [1,7,NH(2)-(15)N(3)-2-(13)C]-guanine, which served as an isotope "tag" to enable specific quantification of guanine lesions originating from that position. After incubation with NNK diazohydroxides, HPLC-ESI(+)-MS/MS analysis was used to determine the yields of NNK adducts at the isotopically labeled guanine and at unlabeled guanine bases elsewhere in the sequence. We found that N7-methyl-2'-deoxyguanosine and N7-[4-oxo-4-(3-pyridyl)but-1-yl]guanine lesions were overproduced at the 3'-guanine bases within polypurine runs, while the formation of O(6)-methyl-2'-deoxyguanosine and O(6)-[4-oxo-4-(3-pyridyl)but-1-yl]-2'-deoxyguanosine adducts was specifically preferred at the 3'-guanine base of 5'-GG and 5'-GGG sequences. In contrast, the presence of 5'-neighboring (Me)C inhibited O(6)-guanine adduct formation. These results indicate that the N7- and O(6)-guanine adducts of NNK are not overproduced at the endogenously methylated CG dinucleotides within the p53 tumor suppressor gene, suggesting that factors other than NNK adduct formation are responsible for mutagenesis at these sites.

Base Sequence↗
PubMed1999

Characterization of volatile compounds from the reaction of 3-hydroxy-2-butanone and ammonium sulfide model system.

The reactions between 3-hydroxy-2-butanone and ammoniun sulfide at 25, 50, 75, 100, 125, and 150 degrees C were studied. Four well-known flavor compounds, 2,4,5-trimethyloxazole, 2,4, 5-trimethyl-3-oxazoline, 2,4,5-trimethylthiazole, and 2,4, 5-trimethyl-3-thiazoline, were identified. Another four interesting intermediate compounds, 2-(1-hydroxyethyl)-2,4, 5-trimethyl-3-oxazoline, 2-(1-mercaptoethyl)-2,4, 5-trimethyl-3-oxazoline, 2-(1-hydroxyethyl)-2,4, 5-trimethyl-3-thiazoline, and 2-(1-mercaptoethyl)-2,4, 5-trimethyl-3-thiazoline, were also identified by GC-EIMS and GC-CIMS. All these intermediate compounds were formed at 25 degrees C. On the other hand, tetramethylpyrazine was the major product with a reaction temperature higher than 100 degrees C.

Acetoin↗
PubMed2005

Uptake and reaction kinetics of acetone, 2-butanone, 2,4-pentanedione, and acetaldehyde in sulfuric acid solutions.

This work presents a study of the uptake of acetone, 2-butanone (methyl ethyl ketone), 2,4-pentanedione, and acetaldehyde by sulfuric acid solutions with an aim at understanding the reactivity of carbonyl compounds present in the atmosphere toward acidic aerosols. Experiments were performed in a rotating wetted-wall reactor coupled to a mass spectrometer at room temperature (298 +/- 3 K) with 0-96 wt % H(2)SO(4) solutions. For all compounds, a reactive uptake was observed at high acidity (>or=64 wt % H(2)SO(4)). The corresponding reactions were found to follow a second-order kinetics, and their rate constants, k (M(-1) s(-1)) were found to increase exponentially with acidity. These rate constants and their variations with acid concentration were in good agreement with the kinetic behavior of acid-catalyzed aldol condensation reported in the organic chemical literature, except for 2,4-pentanedione. The results of this work suggest that aldol condensation should be too slow to account for the enhanced organic aerosol mass observed in smog chamber studies and should have an even smaller contribution under atmospheric conditions. The rate constants of other compounds, such as large aldehydes, remain however to be measured. However, in order to contribute significantly to organic aerosol formation, a liquid phase reaction would have to result in an uptake coefficient of the order of 10(-2).

Journal Article↗
PubMedDate not supplied

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone pulmonary metabolism and tumorigenicity in mice by analogues of the investigational chemotherapeutic drug 4-ipomeanol.

4-Ipomeanol (IPO) is an investigational chemotherapeutic drug with specific toxicity toward the lung. It is metabolically activated to reactive intermediates by cytochrome P450 enzymes present in Clara cells. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a highly carcinogenic tobacco-specific nitrosamine with organo-specificity for the lung. Like IPO, which it resembles structurally, it is metabolically activated by cytochrome P450 enzymes of rat Clara cells. We synthesized nontoxic analogues of IPO and tested their activities as inhibitors of the metabolism and tumorigenicity of NNK. The IPO analogues synthesized were 4-hydroxy-1-phenyl-1-pentanone (HPP), 7-hydroxy-1-phenyl-1-octanone (HPO), 4-hydroxy-1-(2-thienyl)-1-pentanone (HTP), and 4-hydroxy-1-(3-pyridyl)-1-pentanone (HPYP). When added to A/J mouse lung microsomal incubations, all compounds significantly inhibited the oxidative pathways of NNK metabolism--alpha-hydroxylation and pyridine N-oxidation--to varying extents. Inhibition of carbonyl reduction of NNK was generally less effective. Inhibition of alpha-hydroxylation by IPO, HPP, and HTP was more pronounced in incubations with lung microsomes than with liver microsomes. None of the IPO analogues showed significant toxicity when given to A/J mice at a dose of 25 mumol; IPO itself was lethal at this dose. HPP and HPO, at doses of 25 mumol, significantly inhibited lung tumor multiplicity in mice treated with NNK; the other analogues and IPO itself were ineffective. The results of this study provide new leads for development of inhibitors of NNK metabolism and chemical probes for the active site of P450 enzymes in Clara cells.

Animals↗
PubMed2002

Investigation of the role of lipoxygenase in bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human lung.

4-Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogen believed to play a role in human lung cancer. Bioactivation of NNK involves alpha-carbon hydroxylation that could be catalyzed by cytochrome P450, hemoglobin, and lipoxygenases (LOX). In the present study, the role of LOX in NNK bioactivation was investigated. Formation of keto acid, the endpoint metabolite of alpha-methylene NNK hydroxylation, was observed in human lung cytosols incubated with 4.2 microM [5-(3)H]NNK (N = 6). Following concanavalin A affinity chromatography to enrich human lung lipoxygenase (HLLO), the fraction containing cytosolic components less LOX (fraction 1) retained the ability to bioactivate NNK. Although enriched HLLO exhibited the characteristic dioxygenase and hydroperoxidase activities, it did not bioactivate NNK. The LOX inhibitor nordihydroguaiaretic acid inhibited dioxygenase activity of HLLO by 83 +/- 19% (P < 0.05, N = 6), but did not inhibit keto acid formation in the crude cytosols (N = 6, P > 0.05). Failure of soybean LOX to catalyze NNK bioactivation supported the results observed in human lung cytosols, and failure of chemically generated alkylperoxyl radicals to bioactivate NNK further suggested that the dioxygenase activity of LOX is not likely to be involved in NNK bioactivation. Horseradish peroxidase and myeloperoxidase catalyzed NNK bioactivation were also nondetectable. Our results demonstrate that, although human lung cytosols can bioactivate NNK to form keto acid, LOX is not involved. We have attributed the ability of crude human lung cytosols to bioactivate NNK to hemoglobin. The inhibitory effect of 1-aminobenzotriazole and arachidonic acid on keto acid formation in the crude cytosols and in fraction 1, respectively (P < 0.05, N = 6), is consistent with hemoglobin-catalyzed NNK bioactivation.

Aged↗