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PubMed1996

Induction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) activation in rat lung microsomes by chronic ethanol consumption and repeated running exercise.

The effects of both chronic ethanol consumption and repeated exercise on metabolism of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by rat lung microsomes were investigated. Keto aldehyde production was significantly enhanced 52% and 98%, respectively, by the ethanol and exercise, as was keto alcohol production (72% and 76%). 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) production was significantly enhanced only by the exercise (+32%). The combined treatment enhanced the keto alcohol production by 39%, indicating non-additive effects on cytochrome P450 (CYP) isozymes by the different treatments. Immunoblot and metabolic studies revealed an increased activity and content of CYP1A2 and CYP2B induced by the ethanol and exercise treatments as well as an induction of CYP2E1 proteins by the ethanol and combined treatments. These results indicate that both ethanol consumption and running exercise enhance NNK activation by increasing the expression of the CYP enzymes responsible for NNK activation.

Alcohol Drinking↗
PubMed1996

Inhibition of metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by limonene.

Previous work by others shows that d-limonene (LIM) inhibits carcinogen-induced lung tumorigenesis in mice and strongly suggests that LIM can inhibit the metabolic activation of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thus, in the current study, the ability of LIM and other monoterpenes to inhibit the activation of the tobacco-specific NNK was examined in murine pulmonary and hepatic microsomes after addition in vitro or administration in vivo. LIM inhibited the metabolic activation of NNK in both pulmonary and hepatic microsomes. Perillyl alcohol was a more potent inhibitor than LIM, while p-menth-1-ene was equipotent with LIM. After administration of LIM, limonene 1,2-oxide, or perillyl alcohol in vivo, significant inhibition of cytochrome P450-mediated metabolites (NNK N-oxide and HPB) was found at 1 and 4 h after administration of monoterpene. These results indicate that LIM and other monoterpenes are effective inhibitors of NNK metabolic activation, and that other monoterpenes such as perillyl alcohol may be effective chemopreventive agents against NNK-induced lung tumorigenesis.

Animals↗
PubMed2003

Effects of nicotine infusion on the metabolism of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung carcinogen in the rat and believed to be a causative agent for lung cancer in smokers. To exert its carcinogenic potential NNK is metabolically activated by cytochrome P450-catalyzed alpha-hydroxylation. Nicotine and NNK share metabolic pathways. The purpose of this study was to determine whether nicotine alters the fraction of NNK undergoing activation to carcinogenic metabolites. Rats received acute (36 h) or chronic (2 week) s.c. infusions of nicotine at rates producing serum nicotine concentrations 2-3 times the usual venous nicotine concentrations measured in smokers. A single dose of [5-3H]-NNK was administered i.p. 24 h prior to the end of each infusion. Urine was collected for 24 h thereafter and NNK metabolites quantified by radioflow HPLC. Neither acute nor chronic nicotine infusion had any effect on the extent of NNK metabolism by alpha-hydroxylation. These data suggest that nicotine infusion, at rates simulating the higher doses of nicotine replacement therapy now being studied for smoking cessation, neither induces nor inhibits NNK metabolism appreciably and therefore should not alter the formation of carcinogenic NNK metabolites.

Animals↗
PubMed2004

Inhibitory effects of 7-hydroxy-3-methoxy-cadalene on 4-(methylinitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice.

The present study was undertaken to estimate the effect of 7-hydroxy-3-methoxycadalene (cadalene) extracted from Zelkova serrata on 4-(methylinitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. Twenty mice received orally NNK at a dose of 65 microg/ml water for 7 weeks following by free feeding of a commercial diet not containing cadalene for 2 weeks. Control group was maintained without NNK and cadalene administration and/or treatment groups with NNK and cadalene (6.25, 25, 100 mg/kg feed) feeding for 25 weeks. Lung tumors were induced by NNK at incidence ranging from 10 to 45%. Cadalene treatment (100 mg/kg feed) group significantly reduced the incidence of adenomas from 45 to 10% (P < 0.05), and other cadalene treatment group decreased cancer incidences in a concentration dependent manner. The results of our study strongly indicate that cadalene is capable of inhibiting development of NNK-induced lung tumorigenesis in A/J mice.

Administration, Oral↗
PubMed2006

Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer.

Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer. Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated. To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke. Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions. The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans. In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions. Furthermore, the expression of proliferating cellular nuclear antigen increased markedly in both gross tumors and preneoplastic lesions in the lungs. In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer.

Adenocarcinoma↗
PubMed2006

Flavonoids suppresses the enhancing effect of beta-carotene on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A549 cells.

This study investigated the individual and combined effects of beta-carotene with a common flavonoid (naringin, quercetin or rutin) on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-related carcinogen in human. A human lung cancer cell line, A549, was pre-incubated with beta-carotene, a flavonoid, or both for 1h followed by incubation with NNK for 4 h. Then, we determined DNA strand breaks and the level of 7-methylguanine (7-mGua), a product of NNK metabolism by cytochrome P450 (CYP). We showed that beta-carotene at 20 microM significantly enhanced NNK-induced DNA strand breaks and 7-mGua levels by 90% (p < 0.05) and 70% (p < 0.05), respectively, and that the effect of beta-carotene was associated with an increased metabolism of NNK by CYP because the concomitant addition of 1-aminobenzotriazole, a CYP inhibitor, with beta-carotene to cells strongly inhibited NNK-induced DNA strand breaks. In contrast to beta-carotene, incubation of cells with naringin, quercetin or rutin added at 23 microM led to significant inhibition of NNK-induced DNA strand breaks, and the effect was in the order of quercetin > naringin > rutin. However, these flavonoids did not significantly affect the level of 7-mGua induced by NNK. Co-incubation of beta-carotene with any of these flavonoids significantly inhibited the enhancing effect of beta-carotene on NNK-induced DNA strand breaks; the effects of flavonoids were dose-dependent and were also in the order of quercetin > naringin > rutin. Co-incubation of beta-carotene with any of these flavonoids also significantly inhibited the loss of beta-carotene incorporated into the cells, and the effects of the flavonoids were also in the order of quercetin > naringin > rutin. The protective effects of these flavonoids may be attributed to their antioxidant activities because they significantly decreased intracellular ROS, and the effects were also in the order of quercetin > naringin > rutin. These in vitro results suggest that a combination of beta-carotene with naringin, rutin, or quercetin may increase the safety of beta-carotene.

DNA Damage↗
PubMed2006

The organoselenium compound 1,4-phenylenebis(methylene)selenocyanate inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorgenesis and enhances glutathione-related antioxidant levels in A/J mouse lung.

Selenium, in the form of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) but not Se-enriched yeast (Se-yeast), was highly effective at inhibiting lung tumors induced by the tobacco specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice and at reducing NNK-induced DNA methylation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the lung. Our goal was to determine if p-XSC but not Se-yeast is effective at inducing levels of glutathione (GSH)-related antioxidants and reducing markers of GSH oxidation in the NNK-induced lung tumor model. In the first bioassay, 6-week-old mice were fed either control or experimental diets (containing 10 ppm as selenium from p-XSC or Se-yeast) and, beginning at 8 weeks of age, received NNK (3 micromol) by gavage once weekly for 8 weeks. After 18 weeks, p-XSC significantly reduced NNK-induced tumor burden by 74% (10.4 +/- 6.0 versus 2.7 +/- 1.5 tumors/mouse, P < 0.001) and tumor incidence from 96% to 68% (P < 0.01), whereas, Se-yeast had no effect. Lung GSH levels were unchanged by either NNK or Se-yeast, but were increased 70% in mice treated with both NNK and p-XSC (P < 0.01) and 41% in mice treated with p-XSC alone. In the second bioassay, the time course of effects of p-XSC was examined. As early as one week after initiation of p-XSC feeding lung and blood selenium levels were increased nearly six- and two-fold, respectively. Increases of 120% for GSH and 65% for Cys were observed in p-XSC groups compared to controls within one week after initiation of p-XSC feeding (P < 0.01). The levels of protein-bound:free GSH ratios and Cys ratios were significantly decreased in p-XSC-treated mice, regardless of NNK status, suggesting a decrease in the levels of oxidative stress. Altogether, these results indicate that p-XSC is a potent inducer of GSH and related thiol antioxidants in the lung leading to decreased levels of oxidative stress and suggest that p-XSC inhibits tumor formation, in part, by protecting against oxidative damage.

Animal Feed↗
PubMed2006

Formamidopyrimidine adducts are detected using the comet assay in human cells treated with reactive metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most lung-specific of the carcinogens present in tobacco smoke. Its bioactivation in cells leads to a small amount of methylation or pyridyloxobutylation DNA damage. Considering its great sensitivity, the comet assay seems a technique of choice to investigate NNK-related damage. Several strategies were used to impart some specificity to the assay: (1) using analogs that produce a limited variety of DNA lesions, as they mimic either the methylation or the pyridyloxobutylation pathway; (2) using cells with different bioactivation abilities; (3) using alkali conversion and/or enzymes specific for cleaving particular classes of damage; (4) using different lysis conditions to convert a specific class of DNA lesions into enzyme-sensitive lesions. We determined that several NNK-associated lesions can be detected with some specificity with the comet assay. For the methylation pathway, they are AP sites and the more frequent formamidopyrimidine (fapy) adducts. These fapy adducts correspond to N7-methylguanines generated in the cells that were ring-opened during the assay by the lysis solution at pH 10. For the pyridyloxobutylation pathway, alkylphosphotriesters and a roughly equal frequency of fapy sites were detected. By analogy to the methylation damage, these fapy adducts are thought to be the ring-opened form of N7-pyridyloxobutylguanines (N7-pobG). N7-pobG are unstable and this constitutes the first indirect demonstration of their formation in cells. But contrary to N7-m-fapy, the lysis time or pH did not influence the frequency of N7-pob-fapy adducts detected, suggesting that they already exist in the cells and are not related to the experimental conditions. These N7-pob-fapy have a strong mutagenic potential and we think that the comet assay, in spite of its limitations, is a good way to study them considering their low frequency and the inherent instability of the adduct from which they originate.

Carcinogens↗
PubMed2004

Mutations induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lacZ and cII genes of Muta Mouse.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) found in chewing tobacco, snuff, cigarettes, and cigars is a tobacco-specific nitrosamine and classified as a possible human carcinogen (Class 2B) by the International Agency for Research on Cancer (IARC). NNK given intraperitoneally was seen to induce lung and liver adenomas. To evaluate the genotoxicity of NNK in vivo, NNK was intraperitoneally administered to Muta Mouse at two concentrations (125 and 250 mg/kg, once a week for 4 weeks) followed by the measurement of mutant frequencies in the lacZ and cII genes from lung and liver in the same mice. Characterization of the types of the mutation was determined by sequencing the cII genes from mutant plaques. The mutant frequencies in both target genes from both organs dose-dependently increased up to 10 times compared to those of the control group. For the types of mutations, the ratio of the G:C to A:T mutation in the total number of mutants was less than the ratio of A:T to T:A and A:T to C:G transversion, contrary to a previous report. The A:T to T:A transversion was the most highly induced mutation both in the lung and liver cII genes. The increasing rate of mutant frequencies in lung and liver over the vehicle control was 55 and 56 times, respectively, while the increasing rate of G:C to A:T transition was only 1.9 and 2.8 times, respectively. These observations show that NNK predominantly induces DNA adducts leading to A:T to T:A and/or A:T to C:G mutations in the transgene.

Animals↗
PubMed2005

Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation.

Cigarette smoke contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. Nicotine is one of the major components of the cigarette smoke and the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen. Here, we demonstrated that NNK stimulated cell proliferation in normal human bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). Cells exposed to NNK resulted in an increase in the level of cyclin D1 protein (as early as 3-6 h). Increased phosphorylation of the Rb Ser(795) was detected at 6-15 h after NNK treatment and thereby promoted cells entering into the S phase (at 15-21 h). The increased cyclin D1 protein level was induced through activation of the transcription factor, nuclear factor kB (NFkappaB), in the NHBE cells. Treatment of the NHBE cells with PD98059, an ERK1/2 (extracellular signal-regulated protein kinase)-specific inhibitor, specifically suppressed the NNK-induced IkappaBalpha phosphorylation at position 32 of the serine residue, suggesting that the ERK1/2 kinase was involved in the IkappaBalpha phosphorylation induced by NFkappaB activation. To determine whether the NNK-induced NFkappaB activation and cyclin D1 induction were also observed in vivo, A/J mice were treated with NNK (9.1 mg) for 20 weeks and the results showed a significant induction of cyclin D1 and NFkappaB translocation determined by immunoblotting analyses. We further demonstrated that the nicotine acetylcholine receptor (nAchR), which contains the alpha3-subunit, was the major target mediating NNK-induced cyclin D1 expression in the NHBE cells. In summary, our findings demonstrate for the first time that NNK could stimulate normal human bronchial cell proliferation through activation of the NFkappaB, which in turn up-regulated the cyclin D1 expression.

Bronchi↗
PubMed2001

Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta.

4-Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) has been identified as one of the strongest nitrosamine carcinogens in tobacco products in all species tested. Carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. In previous investigations, we have identified a microsomal NNK carbonyl reductase as being identical to 11beta-hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Recently, we provided evidence that carbonyl reduction of NNK does also take place in cytosol from mouse and human liver and lung. In human liver cytosol, carbonyl reductase, a SDR enzyme, and AKR1C1, AKR1C2 and AKR1C4 from the aldo-keto reductase (AKR) superfamily were demonstrated to be responsible for NNK reduction. Since NNK and/or its metabolites can diffuse through the placenta and reach fetal tissues, we now investigated NNK carbonyl reduction in the cytosolic fraction of human placenta in addition to that in microsomes. Concluding from the sensitivity to menadione, ethacrynic acid, rutin and quercitrin as specific inhibitors, mainly carbonyl reductase (EC 1.1.1.184) seems to perform this reaction in human placenta cytosol. The presence of carbonyl reductase was confirmed by RT-PCR. This is the first report to provide evidence that NNAL formation in placenta is mediated by carbonyl reductase.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2001

The effect of a 2-h exposure to cigarette smoke on the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induces lung adenomas in A/J mice following a single intraperitoneal (i.p.) injection. However, inhalation of mainstream cigarette smoke does not induce or promote NNK-induced lung tumors in this mouse strain purported to be sensitive to chemically-induced lung tumorigenesis. The critical events for NNK-induced lung tumorigenesis in A/J mice is thought to involve O(6)-methylguanine (O(6)MeG) adduct formation, GC-->AT transitional mispairing, and activation of the K-ras proto-oncogene. The objective of this study was to test the hypothesis that a smoke-induced shift in NNK metabolism led to the observed decrease in O(6)MeG adducts in the lung and liver of A/J mice co-administered NNK with a concomitant 2-h exposure to cigarette smoke as observed in previous studies. Following 2 h nose-only exposure to mainstream cigarette smoke (600 mg total suspended particulates/m(3) of air), mice (n=12) were administered 7.5 micromol NNK (10 microCi [5-3H]NNK) by i.p. injection. A control group of 12 mice was sham-exposed to HEPA-filtered air for 2 h prior to i.p. administration of 7.5 micromol NNK (10 microCi [5-3H]NNK). Exposure to mainstream cigarette smoke had no effect on total excretion of NNK metabolites in 24 h urine; however, the metabolite pattern was significantly changed. Mice exposed to mainstream cigarette smoke excreted 25% more 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) than control mice, a statistically significant increase (P<0.0001). Cigarette smoke exposure significantly reduced alpha-hydroxylation of NNK to potential methylating species; this is based on the 15% reduction in excretion of the 4-(3-pyridyl)-4-hydroxybutanoic acid and 42% reduction in excretion of 4-(3-pyridyl)-4-oxobutanoic acid versus control. Detoxication of NNK and NNAL by pyridine-N-oxidation, and glucuronidation of NNAL were not significantly different in the two groups of mice. The observed reduction in alpha-hydroxylation of NNK to potential methylating species in mainstream cigarette smoke-exposed A/J mice provides further mechanistic support for earlier studies demonstrating that concurrent inhalation of mainstream cigarette smoke results in a significant reduction of NNK-induced O(6)MeG adduct formation in lung and liver of A/J mice compared to mice treated only with NNK.

Animals↗
PubMed1999

The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism.

Metabolism of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats was compared to metabolism in primary lung and liver cells. Untreated rats and rats pretreated with phenobarbital, acetone or phenethyl isothiocyanate (PEITC) were used for all experiments. Also the influence of [-]-1-methyl-2-[3-pyridyl]-pyrrolidine (nicotine) administered concomitantly with NNK, or incubated with isolated cells, upon NNK metabolism was investigated and found to be only marginal upon alpha-hydroxylation and pyridine N-oxidation in vivo. In hepatocytes nicotine inhibited NNK pyridine N-oxidation, alpha-hydroxylation and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), whereas in lung cells the influence of nicotine was not as pronounced. In vivo phenobarbital induced alpha-hydroxylation and pyridine N-oxidation. In vitro the effects of the modulators were most pronounced upon hepatocytes, where phenobarbital greatly induced pyridine N-oxidation and PEITC inhibited alpha-hydroxylation. NNAL was conjugated to its beta-glucuronide in lung cells at four times higher rates than in hepatocytes. The ratios of the sum of N-oxides to the sum of alpha-hydroxylation products in vivo were similar to those in lung cells, especially at low NNK concentrations (1 microM), while in hepatocytes alpha-hydroxylation was more pronounced. The same correlation of metabolism in isolated lung cells with whole rats was observed if oxidative NNAL metabolism was related to oxidative NNK metabolism. Here hepatocytes showed a much higher formation of NNAL oxidation products than either lung cells formed, or rats excreted in urine. This was true despite a lower rate of metabolism in the lung than in liver if based on cell number, the rate based on mg protein was four times higher in lung than liver. Only after phenobarbital treatment was the contribution of hepatic metabolism to excreted metabolites important. In conclusion the lung which is also the target of NNK carcinogenesis, and not the liver, is the organ with the most important contribution to NNK and NNAL metabolism at concentrations relevant to human exposure.

Animals↗
PubMed2002

Effect of nicotine, cotinine and phenethyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in the Syrian golden hamster.

The effect of nicotine, cotinine and phenethyl isothiocyanate (PEITC) on metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was studied in the Syrian golden hamster. Urinary metabolite profiles were determined in 24 h urine after a single subcutaneous (s.c.) administration of [5-(3)H]NNK (80 nmol/kg, s.c.). Co-administration of either a 500-fold higher dose of nicotine (40 micromol/kg, s.c.) or a 5000-fold higher dose of cotinine (400 micromol/kg, s.c.) significantly (P<0.001) reduced metabolic activation of NNK by alpha-hydroxylation to 85 and 71% of control, respectively. Co-administration of a 300-fold higher dose of PEITC (1 micromol/g diet) slightly reduced alpha-hydroxylation of NNK (94% of control). Metabolism of NNK by reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased by nicotine (155%), and significantly increased by cotinine (670%, P<0.001) and PEITC (219%, P<0.01). Detoxification of NNAL by glucuronidation was also increased by all three test agents. Detoxification of NNK and NNAL by N-oxidation was marginally increased by nicotine, reduced by PEITC, and significantly reduced by cotinine. The urinary metabolite profiles suggest that nicotine, which occurs in concentrations up to 30000-fold higher than NNK in mainstream cigarette smoke, and cotinine, its proximal metabolite, may have a significant protective effect against in vivo metabolic activation of NNK.

Animals↗
PubMed1999

Carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cytosol of mouse liver and lung.

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects, NNK requires metabolic activation which is supposed to occur via alpha-hydroxylation by cytochrome P450 enzymes. Carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. Therefore, NNK carbonyl reducing activity is crucial for NNK inactivation since it initiates the final excretion of this lung carcinogen. Until the present work, studies on NNK metabolism have focused exclusively on microsomal fractions, and several cytochrome P450 enzymes have been shown to be involved in alpha-hydroxylation of NNK. In addition, 11beta-hydroxysteroid dehydrogenase type 1(11beta-HSD1) which is located in the endoplasmic reticulum of the cell has been identified to catalyze the carbonyl reduction of NNK in microsomes. In this study, we provide evidence that carbonyl reduction of NNK does also take place in the cytosolic fraction of mouse liver and lung, and that cytosolic carbonyl reductase contributes to the detoxification of NNK. At a fixed substrate concentration of 1 mM NNK, the specific activity of cytosolic NNAL formation amounts to 72% (liver) and 28% (lung) compared with that in the respective microsomal fractions. Although considerable NNK carbonyl reduction occurred with NADH, the preferred cosubstrate in cytosol is either NADPH or an NADPH-regenerating system. Due to the inhibitor sensitivity to menadione, ethacrynic acid, dicoumarol and quercitrin, it is concluded that carbonyl reductase (EC 1.1.1.184) is mainly responsible for NNAL formation in liver and lung cytosol. The expression of cytosolic carbonyl reductase and microsomal 11beta-HSD1 was established on the mRNA level by reverse transcription-PCR in both liver and lung. Enzyme kinetic studies revealed a nonsaturable Michaelis-Menten kinetic of NNK carbonyl reduction in cytosol. Possibly some other cytosolic NNK carbonyl reducing enzymes are also involved in NNAL formation. In conclusion, this is the first report to show that carbonyl reduction of NNK does occur in cytosol. Further studies with purified enzyme preparations are needed to explore the detailed contribution of the cytosolic enzymes participating in the final elimination of this lung carcinogen.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2000

Use of precision-cut tissue slices in organ culture to study metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by hamster lung, liver and kidney.

The pharmacokinetics of in vitro metabolism of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; concentration range 0.03-250 microM) and its proximal metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; 0.04-250 microM), were determined in Syrian golden hamster liver, lung, and kidney tissue slices in organ culture under identical experimental conditions. In the lung, a target organ for NNK animal carcinogenesis, total NNK metabolism was relatively low (maximum 23%) and oxidative metabolism by alpha-hydroxylation to DNA-reactive intermediates accounted for 13-31% of metabolism. The liver, a non-target organ for NNK carcinogenesis, showed the highest capacity to metabolise NNK (total metabolism 80%), and alpha-hydroxylation accounted for 12-25% of metabolism. The kidney, another non-target organ, also showed a low capacity for NNK metabolism (maximum 32%) and alpha-hydroxylation accounted for <3% of metabolism. Detoxification of NNK by pyridyl N-oxidation was similar in lung (5-22%) and liver (5-23%), and negligible in kidney (<2%), while carbonyl reduction of NNK to NNAL was greatest in the kidney (95-100%), followed by liver (59-79%) and lung (47-81%). NNAL is devoid of biological activity in the hamster and total metabolism was about tenfold lower than that of NNK in all tissues (<13% liver; <4% lung and kidney). In the liver, alpha-hydroxylation was the predominant pathway of NNAL metabolism at almost all concentrations (31-68% of total metabolism), whereas N-oxidation prevailed in the kidney (47-68%). In the lung, a concentration dependent decrease in the relative amount of alpha-hydroxylation (23-72%) with increasing NNAL concentrations occurred at the expense of N-oxidation (25-72%). Little or no metabolism of NNAL back to NNK was evident in any tissue.

Animals↗
PubMed2000

Failure of dietary lyophilized strawberries to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-and benzo[a]pyrene-induced lung tumorigenesis in strain A/J mice.

In the present study, we examined the ability of lyophilized strawberries in the diet to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in the A/J mouse. Groups of 20 mice were administered purified AIN-76A diet containing 10% lyophilized strawberries 1 week before carcinogen dosing, and for the duration of the study. NNK was administered by i.p. injection in five, 0.414 mg doses. B[a]P was administered by gavage in five, 0.2 mg doses. At 20 weeks, there were no significant differences in tumor incidence or tumor multiplicity between the NNK+10% lyophilized strawberry group and the NNK control group. Similarly, at 24 weeks, there were no differences in tumorigenesis between the B[a]P+10% lyophilized strawberry group and the B[a]P control group. Therefore, lyophilized strawberries at 10% in the diet failed to inhibit NNK- and B[a]P-induced mouse lung tumorigenesis.

Adenoma↗
PubMed2000

Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung carcinogens present in tobacco smoke. A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 micromol/mouse) and NNK (3 micromol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks. Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after carcinogen administration. Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model. Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver. Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver. Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPX(Se)), GST-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver. These studies suggest that the chemopreventive efficacy of p-XSC, when fed during carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these carcinogens, and the induction of specific phase II enzymes involved in their detoxification. The mechanisms that account for the effect of p-XSC when fed after carcinogen administration remain to be determined.

Animals↗