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PubMed2006

Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine.

The present study investigated the inhibitory effects of Polyphenon E [a standardized green tea polyphenol preparation containing 65% (-)-epigallocatechin-3-gallate] and caffeine on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor progression from adenoma to adenocarcinoma. Female A/J mice were treated with a single dose of NNK (103 mg/kg body weight, i.p.) and kept for 20 weeks for the mice to develop lung adenomas. The mice were then given a solution of 0.5% Polyphenon E or 0.044% caffeine as the sole source of drinking fluid until week 52. Both treatments significantly decreased the number of visible lung tumors. Histopathologic analysis indicated that Polyphenon E administration significantly reduced the incidence (by 52%) and multiplicity (by 63%) of lung adenocarcinoma. Caffeine also showed marginal inhibitory effects in incidence and multiplicity of adenocarcinoma (by 48% and 49%, respectively). Markers of cell proliferation, apoptosis, and related cell signaling were studied by immunohistochemistry, and the labeling index and staining intensity were quantified by the Image-Pro system. Polyphenon E and caffeine treatment inhibited cell proliferation (by 57% and 50%, respectively) in adenocarcinomas, enhanced apoptosis in adenocarcinomas (by 2.6- and 4-fold, respectively) and adenomas (both by 2.5-fold), and lowered levels of c-Jun and extracellular signal-regulated kinase (Erk) 1/2 phosphorylation. In the normal lung tissues, neither agent had a significant effect on cell proliferation or apoptosis. The results show that tea polyphenols (and perhaps caffeine) inhibit the progression of NNK-induced lung adenoma to adenocarcinoma. This effect is closely associated with decreased cell proliferation, enhanced apoptosis, and lowered levels of c-Jun and Erk1/2 phosphorylation.

Adenocarcinoma↗
PubMed2006

Uptake of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by Moldovan children.

The evidence of an association between childhood exposure to environmental tobacco smoke (ETS) and an increased risk of lung cancer is inconsistent. However, taking into account the existing association between lung cancer and adulthood ETS exposure, it is plausible that children exposed to ETS also would be at risk of developing lung cancer later in life. In this study, we investigated the uptake by Moldovan children of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the sum of the NNK metabolites, NNAL, and its O-glucuronide and N-glucuronide (NNAL-Glucs) in urine. We also measured urinary cotinine and its glucuronide (total cotinine). Total NNAL was detected in 69 of 80 samples, including those that were low in cotinine (<5 ng/mL). The mean+/- SD level of total NNAL (0.09+/- 0.077 pmol/mL) was comparable with those observed in previous studies of children and adults exposed to ETS. Total NNAL correlated with total cotinine (r=0.8, P<0.0001). The mean+/- SD levels of total NNAL and total cotinine were higher in children who were exposed to ETS (0.1+/- 0.08 and 109+/- 126 pmol/mL, respectively) than in those who were classified as unexposed to ETS based on questionnaire data (0.049+/- 0.016 pmol/mL and 0.043+/- 0.040 nmol/mL). The results of this study for the first time show widespread and considerable uptake of nicotine and the tobacco-specific lung carcinogen NNK in Moldovan children. These results should be useful in heightening the awareness of the dangers of smoking and ETS exposure in this eastern European country.

Adenocarcinoma↗
PubMedDate not supplied

Toxicology and carcinogenesis studies of ozone and ozone 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone in Fischer-344/N rats.

The purpose of this study was to evaluate the toxicity and potential carcinogenicity or cocarcinogenicity of ozone exposure in rats. Fischer-344/N (F-344/N) rats were exposed 6 hr/day, 5 days/wk, to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 2-yr and lifetime exposures. The cocarcinogenicity study included subcutaneous administration of 0, 0.1, or 1.0 mg/kg body weight of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and inhalation of 0 or 0.5 ppm ozone to male rats. NNK was administered by subcutaneous injections 3 times per week for the first 20 wk with ozone inhalation exposure. The ozone inhalation exposure was for 2 yr (104 wk), including the first 20 wk of NNK treatment and continuing for 84 wk after the last NNK injection. Ozone exposure caused a concentration-related increase in inflammation of the centriacinar region of the lung. There was also increased fibrosis and an extension of the bronchiolar epithelium in these centriacinar regions to involve the proximal alveoli. There was no increased incidence of neoplasms at any site, including the lung, that was associated with ozone exposure. Rats administered 1.0 mg/kg body weight NNK alone had an increased incidence of bronchiolar/alveolar neoplasms, but this effect was not enhanced by ozone exposure. Ozone exposure for 2 yr and lifetime was associated with site-specific toxic alterations in the nasal passage and lung similar to those previously described for short-term exposures. While there was significant attenuation of the pulmonary lesions as compared to short-term exposures, lesions persisted in the lifetime study and there was evidence of a mild progressive fibrosis. We conclude that under the conditions of these studies: (a) ozone exposure is not carcinogenic to either male or female F-344/N rats, (b) ozone does not enhance the incidence of pulmonary neoplasms in F-344/N rats exposed to a known pulmonary carcinogen (NNK), and (c) mild site-specific toxic lesions characteristic of ozone exposure persist in the nasal passage and lung throughout the lifetime of the rat with continued ozone exposure.

Administration, Inhalation↗
PubMed2003

Comparison of the chemopreventive efficacies of 1,4-phenylenebis(methylene)selenocyanate and selenium-enriched yeast on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced lung tumorigenesis in A/J mouse.

Epidemiological studies, clinical intervention trials (including the trial with selenium-enriched yeast by Clark et al. JAMA 276, 1957, 1996) and assays in laboratory animals provide evidence for a protective role of selenium against the development of several cancers, including lung cancer. We have demonstrated that selenium in the form of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a promising chemopreventive agent in the A/J mouse lung tumor model induced with the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); under identical conditions, selenomethionine (SM), a component of selenium-enriched yeast, had no effect. The lack of an effect of SM suggests that other forms of selenium, or selenium-enriched yeast as a whole, are essential for lung cancer prevention; moreover, various species may respond differently to a given form of selenium. Therefore, in this study, we compared the chemopreventive efficacies of p-XSC with selenium-enriched yeast. Groups of 5-wk-old mice were fed either control diet or experimental diet containing p-XSC (5 or 10 ppm as selenium, equivalent to 20% and 40% maximum tolerated dose [MTD], respectively) or selenium-enriched yeast (5 or 10 ppm). Beginning at Wk 7, each mouse received NNK (3 mmol) in 0.1 ml cottonseed oil by intragastric intubation, once weekly for 8 wk. Twenty-six weeks after the first NNK administration, mice were killed and tumors in lung and forestomach were counted. p-XSC at 5 and 10 ppm doses significantly reduced lung tumor induction by NNK from 10.4 -/+ 6.0 (multiplicity) to 2.7 -/+ 1.5 (P < 0.001) and 1.8 -/+ 2.0 (P < 0.0001) respectively, whereas selenium-enriched yeast had no effect. p-XSC at 10 ppm also significantly reduced the incidence level from 96% to 68% (P < 0.01). The amounts of selenium that reach the target organ (lung) after dietary administration of p-XSC (326 -/+ 69 ng Se/g lung tissue) were significantly higher than that from selenium-enriched yeast (34 -/+ 8.5 ng Se/g lung tissue). However, the levels of selenium in plasma from selenium-enriched yeast (620 -/+ 54 ng Se/g plasma) were twofold higher than those from p-XSC (355 -/+ 85 ng Se/g plasma). In biochemical studies, p-XSC was shown to significantly inhibit formation of O6-methylguanine (O6-MG) and 7-methylguanine (7-MG) in the lungs and livers of mice treated with NNK. The lack of effect of selenium-enriched yeast on these lesions agrees with the results of the bioassay. Collectively, the results of this study clearly indicate that as a chemopreventive agent, p-XSC is superior to selenium-enriched yeast under the conditions of the present protocol. The inhibition of DNA methylation and the significantly higher retention of selenium from p-XSC as compared with selenium-enriched yeast in the target organ may in part account for the inhibition of lung tumorigenesis.

Animals↗
PubMed1988

Effect of buflomedil [4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride] on neurotransmitters in the striatum and substantia nigra.

Effect of buflomedil [4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride] administration on central monoaminergic systems was investigated using male Wistar rats. Single administration of buflomedil (300 mg/kg, p.o.) induced a significant increase in the content of homovanillic acid without altering the content of dopamine (DA) and also caused a significant decrease in choline acetyltransferase (ChAT) activity in the corpus striatum. In addition, both L-glutamic acid decarboxylase activity (GAD) and gamma-aminobutyric acid (GABA) content showed a significant decrease in the substantia nigra following a single administration of buflomedil. These results indicate that buflomedil enhances DA turnover in the nigro-striatal DA pathway, possibly by activating nigro-striatal DA neurons, or by suppressing striatal cholinergic interneurons and/or striato-nigral GABAergic neurons.

Amino Acids↗
PubMed1989

Effect of buflomedil (4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy phenyl)-1-butanone hydrochloride) on the function of striatal dopaminergic neurons.

Effect of buflomedil (4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy phenyl)-1-butanone hydrochloride) on the release and uptake of dopamine (DA) and the function of DA receptors in the striatum was investigated using male Wistar rats. In vitro addition of buflomedil (10(-5)-10(-8) M) had no effect on the uptake of [3H]-DA in striatal slices. On the other hand, buflomedil (10(-5)-10(-7) M) increased the spontaneous as well as high K+ (30 mM)-evoked releases of [3H]DA from striatal slices. Buflomedil inhibited the bindings of [3H]SCH23390, [3H]spiperone and [3H]apomorphine to striatal D1, D2 and D3 receptors only at a high concentration. On the other hand, buflomedil inhibited [3H]quinuclidinyl benzilate (QNB) binding to striatal muscarinic cholinergic receptors, which was similar to the action of carbachol. Pretreatment with scopolamine (0.5 mg/kg) in vivo inhibited the facilitation of striatal DA turnover induced by oral administration of buflomedil (300 mg/kg). In contrast, continuous oral administration of buflomedil (30 mg/kg x 7 days) to rats had no significant effect on the specific bindings of [3H]SCH23390, [3H]spiperone, [3H]apomorphine and [3H]QNB to synaptic membrane preparations obtained from the striatum. These results suggest that buflomedil may enhance striatal DA release by stimulating muscarinic cholinergic receptor and that DA receptors may not be involved in the enhancing effect of buflomedil on DA release.

Animals↗
PubMedDate not supplied

A/J mouse lung tumorigenesis by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by arylalkyl isothiocyanates.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important carcinogen found in tobacco and tobacco smoke. It is a potent lung tumorigen in rodents and appears to be involved in human cancer induced by tobacco products. NNK induces lung tumors in A/J mice after a single dose; tumor multiplicity is higher when the mice are maintained on an AIN-76A diet than when they are maintained on NIH-07 diet. This paper reviews our recent research using this single-dose model. Bioassays of deuterium substituted analogues of NNK have demonstrated that methylation of DNA by NNK is an important step in lung tumor induction. Arylalkyl isothiocyanates inhibit the metabolic activation of NNK and consequently inhibit its DNA binding and tumorigenesis. Structure activity studies have demonstrated that increasing alkyl chain length leads to increasing efficacy in prevention of NNK tumorigenesis. Thus, 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate blocked NNK induced lung tumor formation in A/J mice. Lower doses of longer chain arylalkyl isothiocyanates were even more effective as chemopreventive agents.

Animals↗
PubMedDate not supplied

Expression of cell cycle proteins in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumors.

Cyclin D1 dysregulation and differential inactivation of p16INK4a and Rb have been observed in human lung cancer. In chemically induced mouse lung tumors, the p16INK4a gene is a target of inactivation, and Rb is reduced at the mRNA level (Northern blot) although similar at the protein level (Western blot) when compared to normal lung tissues. The expression of cyclin D1, cdk4, p16INK4a, and Rb protein was examined by immunohistochemistry in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumors. Immunohistochemical staining revealed exclusive nuclear staining of both cyclin D1 and cdk4 that was light to moderate in normal mouse lung tissues, but intense in lung adenomas and adenocarcinomas. Western blot analysis confirmed the increased expression of cyclin D1 and cdk4 in lung tumors compared to normal lung. Immunohistochemical analyses of lung tumors showed focal areas which lacked p16INK4a staining. Expression of p16INK4a, as determined by RT-PCR, was variable in lung tumors. Mutations in p16INK4a were not found by SSCP analysis. Immunohistochemical analyses of normal lung tissues showed intense staining for Rb protein in alveolar epithelial cells and in other lung cell types; however, in the lung tumors the staining intensity was reduced and the distribution was altered. Expression of Rb was detected in normal lung tissues but was barely detectable by Northern blot hybridization in lung tumors. Western blot analysis indicated the presence of both hypophosphorylated and hyperphosphorylated Rb protein in lung tumors and in normal lung tissues. These results suggest that alterations in the cell cycle proteins, cyclin D1, cdk4, p16INK4a, and Rb, may play a role in the acquisition of autonomous growth by adenomas. Furthermore, they demonstrate the importance of immunohistochemical studies to examine expression in tissues that contain multiple cell types, such as the lung, and in tumors that by nature are heterogeneous.

Adenocarcinoma↗
PubMed1996

Recent studies on mechanisms of bioactivation and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen.

This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention.

Animals↗
PubMed2000

Activation of voltage-operated Ca2+-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The nicotine-derived tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung cancer in all animal species tested and is thought to contribute significantly to the high lung cancer burden associated with smoking. NNK has recently been identified as a high affinity ligand for neuronal nicotinic acetylcholine receptors comprised of alpha7 subunits (alpha7 nAChR), and expressed in human small cell lung carcinoma (SCLC). As agonist-binding to this receptor in mammalian cells often results in membrane depolarization and activation of voltage-operated Ca2+-channels (VOCCs), we hypothesized that NNK may exert similar effects in SCLC. Using flow cytometry to monitor the influx of Ca2+, reverse transcription polymerase chain reaction (RT-PCR) to determine the expression of VOCC-specific messenger RNA, as well as analysis of DNA synthesis or determination of cell number, our data demonstrate that binding of NNK to the alpha7 nAChR in SCLC cells caused influx of Ca2+ via VOCCs of the L-, N-, and P-type. In turn, this led to a significant increase in DNA synthesis and cell number which was inhibited by a site-selective antagonist for the alpha7 nAChR and by Ca2+-channel blockers of the L-, N-, or P-types of VOCCs. Our findings suggest that the chronic activation of VOCC-mediated Ca2+ influx by NNK in smokers is an important event that may affect numerous Ca2+-dependent signal transduction pathways, thus contributing significantly to the development of SCLC.

Calcium Channels↗
PubMed1999

Metabolism and disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in rhesus monkeys.

Metabolism and disposition of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent rodent lung carcinogen, were studied in rhesus monkeys. In three males receiving a single i.v. dose of [5-3H]NNK (0.72 mCi; 4.6-9.8 microg/kg), urine was collected for 10 days. Within the first 24 h, 86.0 +/- 0.7% of the dose was excreted. NNK-derived radioactivity was still detectable in urine 10 days after dosing (total excretion, 92.7 +/- 0.7%). Decay of urinary radioactivity was biexponential with half-lives of 1.7 and 42 h. Metabolite patterns in urine from the first 6 h closely resembled those reported previously for patas monkeys; end products of metabolic NNK activation represented more than 50% of total radioactivity. At later time points, the pattern shifted in favor of NNK detoxification products (60-70% of total radioactivity in urine), mainly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide conjugates. One female rhesus monkey received a single i.v. dose of [5-3H]NNK (1.72 mCi; 28.4 microg/kg) under isoflurane anesthesia; biliary excretion over 6 h (0.6% of the dose) was 10 times less than predicted by our previously reported rat model. No preferential excretion of NNAL glucuronide was observed in monkey bile. Collectively, these results suggest that the rhesus monkey could be a useful model for NNK metabolism and disposition in humans.

Animals↗
PubMed1999

Increased expression of cyclooxygenase-2 in rat lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: the impact of a high-fat diet.

Aberrant or excessive expression of cyclooxygenase (COX)-2 has been implicated in the pathogenesis of many disease processes, including carcinogenesis. COX-2 expression was immunohistochemically examined in archival samples (D. Hoffmann et al., Cancer Res., 53: 2758-2761, 1993) of lung neoplasms (adenomas, adenocarcinomas, and adenosquamous carcinomas) induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male F344 rats that had been fed either a semipurified AIN-76A diet with high-fat (HF; 23.5% corn oil) or low-fat (LF; 5% corn oil) content. The intensity and extent of COX-2 positivity was graded from 0 (undetectable or negligible expression) to grades 1 (<30% expression), 2 (30-60% expression), 3 (60-90% expression), and 4 (>90% expression). The scoring criteria were similar to those used with specimens from human lung cancers (T. Hida et al., Cancer Res., 58: 3761-3764, 1998). In group 1 (NNK plus HF diet), adenomas, adenocarcinomas, and adenosquamous carcinomas were of mean grades 2, 3, and 4, respectively; in group 2 (NNK plus LF diet), the corresponding mean grades were 1, 1, and 3. Although control rats, given HF (group 3) or LF (group 4) diets but no NNK, developed spontaneous lung tumors, the expression of COX-2 was either negligible (one adenoma of grade 0 in group 3) or of a very low grade (one adenocarcinoma of grade 1 in group 4). In addition, the latency of the tumors in the peripheral lung in assays with NNK is significantly shorter in rats maintained on the HF diet than in those on LF diet. COX-2 expression was not evident in normal lung tissues. We report here for the first time that NNK induces increasingly higher levels of COX-2 expression with progressive stages of lung tumorigenesis when rats are fed the HF diet. The increase in COX-2 expression may be associated with the development of lung tumors induced by NNK. This well-defined animal model is valuable for studying modulation of COX-2 expression in lung carcinogenesis by various factors, including dietary components.

Animals↗
PubMed1999

The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid.

Lung cancer is the leading cause of death in the United States, and it demonstrates a strong etiological association with smoking. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces pulmonary adenocarcinomas (ACs) in laboratory rodents and is considered an important contributing factor to the high lung cancer burden observed in smokers. It has been shown that the development of NNK-induced ACs in mice is reduced by inhibitors of cyclooxygenase and lipoxygenase and that the growth of human AC cell lines is regulated by beta-adrenergic receptors. On the basis of structural similarities of NNK with classic beta-adrenergic agonists, we tested the hypothesis that NNK stimulates the growth of human AC cells via agonist-binding to beta-adrenergic receptors, resulting in the release of arachidonic acid (AA). In support of this hypothesis, radioreceptor assays with transfected CHO cell lines stably expressing the human beta1- or beta2-adrenergic receptor demonstrated high affinity binding of NNK to each of these receptors. Two human AC cell lines expressed beta1- and beta2-adrenergic receptors by reverse transcription-PCR and responded to NNK with the release of AA and an increase in DNA synthesis. Beta-adrenergic antagonists completely blocked the release of AA and increase in DNA synthesis. The cyclooxygenase inhibitor aspirin and the 5-lipoxygenase inhibitor MK-886 both partially inhibited DNA synthesis in response to NNK. Our findings identify the direct interaction of NNK with beta-adrenergic, AA-dependent pathways as a novel mechanism of action which may significantly contribute to the high cancer-causing potential of this nitrosamine. Moreover, NNK may also contribute to the development of smoking-related nonneoplastic disease via this mechanism.

Adenocarcinoma↗
PubMed2000

Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone by cultured monkey lung explants.

The metabolism of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated in short-term cultures of monkey lung. Explants from the lungs of two patas monkeys (Erythrocebus patas) and one cynomolgus monkey (Macaca fascicularis) were incubated with 10 microM [5-(3)H]NNK and aliquots were analyzed for NNK metabolites by HPLC at various time points from 1 to 24 h. F344 rat lung tissue metabolism of NNK was assayed under the same conditions. Substantial amounts of metabolites from the alpha-hydroxylation metabolic activation pathway were detected in all cultures. In two of the monkey lung cultures, these metabolite levels were significantly higher than those formed by other pathways. All cultures also metabolized NNK by pyridine-N-oxidation and carbonyl reduction. The metabolism of NNK by cultured monkey lung was generally similar to that observed in rat lung, indicating that there are not major species differences between rodents and nonhuman primates in pulmonary metabolism of NNK.

Animals↗
PubMed2000

Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in primary cultures of rat alveolar type II cells.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces primarily lung tumors, which are assumed to derive from malignant transformation of alveolar type II (AII) cells within the lung. To elicit its carcinogenic effects, NNK requires metabolic activation by cytochrome P-450 (CYP)-mediated alpha-hydroxylation. Therefore, in this study the metabolism of NNK and expression of the NNK-activating CYP isoform CYP2B1 were investigated in primary cultures of rat AII cells. Although basal expression of CYP2B1 decreased in a time-dependent manner during culture of AII cells, substantial CYP2B1 protein expression was observed in AII cell cultures after the first 24 h. When AII cells were incubated with 0. 05 microM [5-(3)H]NNK, N-oxidation of NNK, which is thought to represent a detoxification pathway, was predominant (42%). alpha-Hydroxylated metabolites resulting from metabolic activation of NNK amounted to 35% of all detected metabolites. However, the proportion of alpha-hydroxylated metabolites decreased to 17% of all detected metabolites when AII cells were incubated with a 100-fold higher concentration of NNK (5 microM). In summary, this study indicates a remarkable activity of cultured AII cells to metabolize NNK, leading to substantial metabolic activation of NNK, which was more pronounced in incubations at low NNK concentration. Because exposure to NNK via cigarette smoking is thought to lead to very low plasma NNK concentrations (1-15 pM), these data suggest that metabolic activation of NNK in cigarette smokers might occur to a larger extent than would be expected according to previous metabolic studies performed with high (micromolar) NNK concentrations.

Animals↗
PubMed2000

Scintigraphic imaging of the hypoxia marker (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; prognox): noninvasive detection of tumor response to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid.

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) and combretastatin A4 phosphate (CA-4-P) markedly inhibit tumor blood flow in mice and are both currently in clinical trial. One of the challenges in clinical evaluation of antivascular agents is the monitoring of tumor blood flow inhibition in individual patients. This study investigates, using mouse models, whether a new marker for tissue hypoxia, (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; Prognox)] has potential for the scintigraphic monitoring of tumor response to antivascular agents. Determination of radioactivity in dissected tissues 3 h after DMXAA (80 micromol/kg) or CA-4-P (227 micromol/kg) was injected indicated that both drugs inhibited blood flow (86RbCl uptake; 84 and 87%, respectively) and increased 99mTc-labeled HL-91 levels (350 and 300%, respectively) selectively in murine RIF-1 tumors. Planar imaging of 99mTc-labeled HL-91 3 h after DMXAA injection showed a dose-dependent increase in tumor levels above a threshold of 50 micromol/kg; this same threshold was observed for the inhibition of tumor blood flow (determined using Hoechst 33342). DMXAA also inhibited blood flow--and increased 99mTc-labeled HL-91 uptake--in MDAH-MCa-4 mouse mammary carcinomas and in NZMN10 human melanoma xenografts. Whether 99mTc-labeled HL-91 might also be useful as a biomarker for tumor cell killing was investigated by clonogenic assay of surviving cells 15 h after imaging 99mTc-labeled HL-91 in RIF-1 tumors. Log cell kill in individual tumors showed a statistically significant linear correlation (P < 0.001) with 99mTc-labeled HL-91 uptake after 60 micromol/kg (r2 = 0.79) and 70 micromol/kg (r2 = 0.44) but not at 80 micromol/kg DMXAA. The lack of correlation at high doses presumably reflects the insensitivity of the tumor-averaged 99mTc-labeled HL-91 signal to small regions in which tumor blood flow is preserved (which will limit log cell kill). The results indicate the potential of 99mTc-labeled HL-91 for the noninvasive imaging of tumor blood flow inhibition by antivascular drugs in humans.

Angiogenesis Inhibitors↗
PubMed2000

Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The human CYP2A subfamily comprises three genes, CYP2A6, CYP2A7, and CYP2A13. CYP2A6 is active toward many carcinogens and is the major coumarin 7-hydroxylase and nicotine C-oxidase in the liver, whereas CYP2A7 is not functional. The function of CYP2A13 has not been characterized. In this study, a CYP2A13 cDNA was prepared by RNA-PCR from human nasal mucosa and was translated using a baculovirus expression system. In a reconstituted system, the expressed CYP2A13 was more active than CYP2A6 in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, and N-nitrosomethylphenylamine but was much less active than CYP2A6 in coumarin 7-hydroxylation. Of particular interest, CYP2A13 was highly active in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, with a catalytic efficiency much greater than that of other human cytochrome P450 isoforms examined previously. The tissue distribution of CYP2A13 was determined with isoform-specific RNA-PCR. CYP2A13 mRNA was detected in liver and a number of extrahepatic tissues, including nasal mucosa, lung, trachea, brain, mammary gland, prostate, testis, and uterus, but not in heart, kidney, bone marrow, colon, small intestine, spleen, stomach, thymus, or skeletal muscle. Quantitative PCR analysis further revealed that CYP2A13 mRNA is expressed at the highest level in the nasal mucosa, followed by the lung and the trachea. Together, these findings suggest that CYP2A13 plays important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the human respiratory tract.

Adolescent↗
PubMed2002

Quantitation of metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone after cessation of smokeless tobacco use.

Two major metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were previously shown to be highly persistent in human urine after cessation of cigarette smoking. We hypothesized that NNK or its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was sequestered in the lung. In this study, we further evaluated this hypothesis by quantifying the NNK metabolites, NNAL and its glucuronides (NNAL-Gluc), in urine and plasma after cessation of smokeless tobacco use, in which NNK is administered p.o. rather than by inhalation. Thirteen male nonsmokers, 11 snuff dippers and 2 tobacco chewers, participated in the study. Urine and plasma were obtained at baseline and at intervals 2-126 days after cessation of smokeless tobacco use. The distribution half-lives t(1/2alpha) (days) of NNAL (1.32 +/- 0.85 versus 3.35 +/- 1.86) and NNAL-Gluc (1.53 +/- 1.22 versus 3.89 +/- 2.43) were significantly shorter in smokeless tobacco users than in smokers. There were no significant differences in the terminal half-lives t(1/2beta) (days) of NNAL (26.3 +/- 16.7 versus 45.2 +/- 26.9) and NNAL-Gluc (26.1 +/- 15.1 versus 39.6 +/- 26.0) in smokeless tobacco users and smokers. Baseline levels as well as renal clearance of the NNK metabolites correlated with number of tins or pouches of smokeless tobacco consumed. Ratios of (S)-NNAL:(R)-NNAL and (S)-NNAL-Gluc:(R)-NNAL-Gluc in urine were significantly (3.1-5.7 times) higher 7 days after cessation than at baseline in both smokeless tobacco users and smokers, indicating stereoselective retention of (S)-NNAL. Collectively, the results of this study suggest that there is a receptor in the human body, possibly in the lung, for (S)-NNAL, the more carcinogenic NNAL enantiomer. These data may have considerable implications for understanding mechanisms of tumor induction by NNK.

Administration, Oral↗