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F L Chung

Publications and source records attributed to F L Chung.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants.

In this study we examined the effects of green tea and its major components, (-)-epigallocatechin gallate (EGCG) and caffeine, on the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. We also studied the effects of green tea and EGCG on O6-methylguanine and 8-hydroxydeoxyguanosine (8-OH-dGuo) formation in lung tissues caused by NNK treatment. Mice were given 2% tea, 560 ppm EGCG, or 1120 ppm caffeine in drinking water for 13 weeks. During this time, NNK (11.65 mg/kg body weight) was administered by gavage three times weekly for 10 weeks from weeks 3 to 12. The bioassay was terminated 6 weeks after the last NNK treatment. Mice treated with NNK developed 22.5 lung adenomas per mouse, whereas NNK-treated mice that drank green tea or EGCG as drinking water developed only 12.2 (P less than 0.01) and 16.1 (P less than 0.05) tumors per mouse, respectively. Mice that drank green tea or caffeine solution showed lower body weight gains, although little difference in water and diet consumption was noted in these groups. While green tea and EGCG exerted little effect on the formation of O6-methylguanine, a critical DNA lesion in NNK lung tumorigenesis, both treatments suppressed the increase of 8-OH-dGuo levels in mouse lung DNA. The inhibition of 8-OH-dGuo formation in lung DNA by green tea and EGCG is consistent with their ability to inhibit lung tumorigenesis by NNK. Because 8-OH-dGuo is a DNA lesion caused by oxidative damage, these results suggest that the mechanism of inhibition by green tea and EGCG in NNK-induced lung tumorigenesis is due at least partly to their antioxidant properties.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1992

New potential chemopreventive agents for lung carcinogenesis of tobacco-specific nitrosamine.

Cigarette smoking is the major cause of lung cancer in humans. The continuous increase in the prevalence of cigarette smoking worldwide demands a practical means to circumvent this serious health problem. Our research has focused on the development of new chemopreventive agents against lung carcinogenicity of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Several aromatic isothiocyanates have been identified as effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Phenethyl isothiocyanate, a natural constituent of cruciferous vegetables, protects F344 rats and A/J mice from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. The alkyl chain length in the aromatic isothiocyanates is an important structural feature for the inhibitory potency. The inhibitory efficacy increases as the alkyl chain elongates up to 6 carbon atoms. Thus, 6-phenylhexyl isothiocyanate is approximately 50 to 100 times more potent than phenethyl isothiocyanate. The remarkable efficiency of 6-phenylhexyl isothiocyanate suggests its potential as a chemopreventive agent in intervention trials. The tissue distribution and excretion of phenethyl isothiocyanate were studied in mice. Two major urinary metabolites were identified as the mercaptopyruvic acid and the N-acetylcysteine conjugates. A urinary marker was developed to quantitate the uptake of phenethyl isothiocyanate in humans after consumption of watercress, a cruciferous vegetable rich in gluconasturtiin, the glucosinolate precursor of phenethyl isothiocyanate. Considering the anticarcinogenic activity of phenethyl isothiocyanate, this marker may eventually be useful in assessing the role of dietary phenethyl isothiocyanate uptake in lung cancer risk.

Adenoma↗
PubMed1992

Effect of frequency of isothiocyanate administration on inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenoma formation in A/J mice.

The abilities of phenethyl isothiocyanate (PEITC) and 6-phenylhexyl isothiocyanate (PHITC) to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenicity, when administered by a standard four-dose protocol or by a single-dose protocol, were determined. Corn oil or isothiocyanates were administered once or for four consecutive days by gavage, with the final (or single) administration of corn oil or inhibitor occurring 2 h prior to a single i.p. injection of NNK (10 mumol/mouse). Sixteen weeks following NNK administration, the experiment was terminated and pulmonary adenomas were quantitated. Pretreatment with PEITC at a dose of 5 mumol or PHITC at a dose of 0.2 mumol resulted in significant reductions of tumor multiplicity compared to control, regardless of whether each isothiocyanate was administered once or four times. For both isothiocyanates, there were no statistically significant differences between dosing frequencies in inhibitory effects on tumor multiplicities and tumor incidences. Furthermore, the results achieved following a single pretreatment with either isothiocyanate were in good agreement with previous results obtained utilizing the four-dose protocol. Thus, it appears that most or all of the inhibitory potential of the four-dose protocol is due to the final dose of isothiocyanate.

Adenoma↗
PubMed1992

Acute toxicity of trans-4-hydroxy-2-nonenal in Fisher 344 rats [corrected].

The potential toxicity of trans-4-hydroxy-2-nonenal (HNE), a product formed in vivo during lipid peroxidation, which is also present in foods, was investigated in Fisher 344 rats. Five groups of five male rats each were given by gavage 1000, 300, 100, 30 or 10 mg/kg body weight HNE dissolved in 0.5 mL corn oil. The sixth group, the control, received corn oil alone. Two rats died 6 and 8 hr after being treated with 1000 mg/kg HNE. These two rats showed extensive acute tubular necrosis of the kidney, but had very little liver damage. Diffuse liver cell necrosis was observed in a dose dependent manner in all the rats killed 14 days after treatment, whereas renal change was mild. Interestingly, body weight of the lowest dosage group was significantly higher than that of the control group at termination of the experiment. The results of this study show that HNE has almost the same toxicity as other enals, such as trans-2-heptenal, and that kidney and liver are the main organs affected by toxicity of HNE. Although animals may have efficient defense systems, such as glutathione, to detoxify low to moderate dosages of HNE, at high doses of HNE this defense system is overwhelmed, resulting in serious renal and hepatic damage.

Administration, Oral↗
PubMed1992

Formation of 7-(4-oxobutyl)guanine in hepatic DNA of rats treated with N-nitrosopyrrolidine.

We have reported previously the formation of two structurally distinct exocyclic guanine adducts (adducts 1 and 6) in liver DNA of F344 rats treated with N-nitrosopyrrolidine (NPYR). In this study, we detected and characterized a previously unidentified guanine adduct in liver DNA of NPYR-treated rats. The structure of this adduct was established as 7-(4-oxobutyl)guanine (adduct 2) by comparison with the synthetic standard and confirmed by NaBH4 reduction to 7-(4-hydroxybutyl)guanine. The level of adduct 2 in liver DNA of F344 rats treated with 450 mg/kg of NPYR by i.p. administration was 643 +/- 9 mumol/mol guanine, approximately one-third of the level of adduct 1. This study is the first to demonstrate the in vivo formation of a formylalkyl-substituted guanine adduct by a nitrosamine.

Animals↗
PubMed1992

Increased 8-oxodeoxyguanosine levels in lung DNA of A/J mice and F344 rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone.

Evidence for the involvement of free radicals in nitrosamine carcinogenesis comes mainly from increased lipid peroxidation as a result of nitrosamine treatment. More direct evidence for nitrosamine-induced oxidative DNA damage has been lacking. In this study we examined the levels of 8-oxodeoxyguanosine or 8-hydroxydeoxyguanosine (8-OH-dG) in tissue DNA of mice and rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Multiple doses of NNK (0.25 or 0.50 mg/mouse, 3 times weekly for 3 weeks) administered by gavage resulted in a significant elevation of 8-OH-dG in lung DNA, from 2.1 to 3.8 adducts/10(5) dG for the lower dose or to 6.6 adducts/10(5) dG for the higher dose, 2 h after the last NNK administration. A single dose treatment of NNK by gavage (4 mg/mouse) also resulted in an increase of this lesion in the lung DNA, however, the increase was not statistically significant. In liver, however, the increase was only significant by multiple doses at the higher dose, from 2.3 to 3.4 adducts/10(5) dG. This lesion appeared to be repaired efficiently. At 4 and 24 h after NNK treatment, the 8-OH-dG levels declined to the basal levels in both liver and lung. A single dose of NNK (20 mg/rat) also caused a significant increase of 8-OH-dG from 3.0 to 5.1 adducts/10(5) dG in rat lung DNA. An increase of 8-OH-dG in liver DNA was also seen, however, it was not statistically significant. Unlike the liver and the lung, the 8-OH-dG levels in rat kidney, a non-target tissue, were inert to NNK treatment. These results provide for the first time direct evidence supporting the role of oxidative DNA damage in NNK lung tumorigenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1992

Ventricular rate-adaptive pacing in the elderly.

The role of ventricular rate-adaptive pacing (VVIR) in the elderly was investigated in 12 patients with a mean age of 85 +/- 2 years (range 75-95 years) with implanted activity-initiated VVIR pacemakers. Although four patients had significant extracardiac diseases, all were capable of independent walking and self care. The pacing rate achieved during structured daily activities (walking, climbing stairs, washing, bed-making and scrubbing floors) were compared with those achieved by 10 age-matched healthy subjects. Apart from the more strenuous activities (ascending stairs and floor-scrubbing), the pacing rates achieved by the patients were comparable to those of the healthy subjects and occurred within an appropriate time. In a 4-weekly randomized, double-blind crossover protocol in the VVI and VVIR pacing modes, all patients underwent assessments in a 12-min walking distance test, a 24 h non-invasive ambulatory blood pressure recording and a symptomatic documentation. During VVIR pacing, the 12-min walking distance was significantly improved compared to VVI pacing (556 +/- 52 vs. 545 +/- 55 m, P less than 0.05). There was no difference between the recorded blood pressure and symptom scores between the two pacing modes, although most patients preferred VVIR pacing (P less than 0.05). It is concluded that VVIR pacing in this elderly population can improve exercise capacity, and the patients' preference for the VVIR mode was documented despite the absence of a measurable difference in symptomatology.

Aged↗
PubMed1992

The use of implantable sensors for the control of pacemaker mediated tachycardias: a comparative evaluation between minute ventilation sensing and acceleration sensing dual chamber rate adaptive pacemakers.

The role of implantable sensors to control pacemaker mediated tachycardias was investigated in 16 patients with two different dual chamber rate adaptive (DDDR) pacemakers, which sensed eiter minute ventilation (DDDR-Meta, nine patients) or body acceleration (Relay, seven patients). Successive atrial sensed events beyond a programmable rate occurring in the absence of detection of exercise by the sensors were considered to represent retrograde conduction or atrial arrhythmias, and the pacemakers responded by either a mode shift from DDDR to ventricular rate adaptive (VVIR) pacing (DDDR-Meta) or by tracking at an interim rate, the so-called conditional ventricular tracking limit (CVTL, Relay). In the unipolar atrial sensing mode, myopotential sensing (MPI) and external chest wall stimulations (CWS) at 250 beats/min were induced to be preferentially sensed by the atrial channel to simulate the conditions of atrial arrhythmias. In the DDD mode, these maneuvers resulted in ventricular responses of 88 +/- 3 beats/min and 110 +/- 3 beats/min for MPI and CWS, respectively. The pacing rate was significantly reduced in the DDDR mode with the sensors correctly detecting and responding to the sensed abnormal atrial signals (68 +/- 5 beats/min during MPI and 71 +/- 5 beats/min during CWS, P less than 0.005 compared with the corresponding DDD rate). One patient with a Relay pacemaker developed spontaneous atrial flutter and the ventricular tracking responses were 140 and 85 beats/min in the DDD and DDDR pacing modes, respectively. Thus MPI and CWS are useful bedside testing methods to assess pacemaker response during atrial arrhythmias. The use of implantable sensors to judge the appropriateness of atrial rate is a new approach to the management of pacemaker mediated tachycardias.

Adult↗
PubMed1992

Atrial arrhythmia management with sensor controlled atrial refractory period and automatic mode switching in patients with minute ventilation sensing dual chamber rate adaptive pacemakers.

Although a long postventricular atrial refractory period (PVARP) may prevent the occurrence of pacemaker mediated tachycardias and inadvertent tracking of atrial arrhythmias in dual chamber (DDD) pacing, the maximum upper rate will necessarily be compromised. We tested the feasibility of using minute ventilation sensing in a dual chamber rate adaptive pacemaker (DDDR) to shorten the PVARP during exercise in 13 patients with bradycardias (resting PVARP = 463 +/- 29 msec) to avoid premature upper rate behavior. Graded treadmill exercise tests in the DDD and DDDR modes at this PVARP resulted in maximum ventricular rates of 98 +/- 8 and 142 +/- 3 beats/min, respectively (P < 0.0001), due to chronotropic incompetence and upper rate limitation in the DDD mode, both circumvened with the use of sensor. In order to stimulate atrial arrhythmias, chest wall stimulation was applied for 30 seconds at a rate of 250 beats/min at a mean unipolar atrial sensitivity of 0.82 mV. Irregular ventricular responses occurred in the DDD mode (the rates at a PVARP of 280 and 463 +/- 29 msec were, respectively 92 +/- 5 and 66 +/- 3 msec; P < 0.0001). In the DDDR mode at a PVARP of 463 +/- 29 msec, regular ventricular pacing at 53 +/- 2 beats/min occurred due to mode switching to VVIR mode in the presence of repetitive sensed atrial events within the PVARP. One patient developed spontaneous atrial fibrillation on follow-up, which was correctly identified by the pacemaker algorithm, resulting in mode switch from DDDR to regular VVIR pacing and preservation of rate response. In conclusion, sensor controlled PVARP allows a long PVARP to be used at rest without limiting the maximum rate during exercise. In addition, to offer protection against retrograde conduction, a long PVARP and mode switching also limit the rate during atrial arrhythmias and allow regular ventricular rate responses according to the physiological demands.

Aged↗
PubMed1992

Initial clinical experience with a single pass VDDR pacing system.

Although ventricular rate adaptive pacing (VVIR) improves exercise capacity and cardiac output compared to constant rate ventricular pacing (VVI), this pacing mode does not provide benefit of atrioventricular (AV) synchrony. We evaluated the use of a custom-built VDDR pacing system using a single pass, ventricular lead, which detects endocavity P wave using a pair of diagonally arranged atrial bipolar (DAB) electrodes. In the VDDR mode, AV synchrony is enabled and the P wave rate is used in conjunction with an accelerometer based activity sensor for rate adaptive pacing. A VDDR pacemaker was implanted in three patients with complete AV block (mean age 63 +/- 1 year) and the mean implantation time was 29 minutes. Mean P wave amplitude was 2.4 mV (1.2-4.2 mV) at implantation and telemetered P wave amplitude was stable over a follow-up of 6 months. At a sensitivity of 0.2 mV, stable P wave sensing was observed during breathing maneuvers, arm swinging, myopotential induction, and Holter recording. Paired exercise tests performed in the VDDR and VVIR modes showed higher cardiac output at rest, during exercise, and in the recovery period in the VDDR pacing mode. Thus VDDR pacing using a single pass lead is superior to VVIR pacing by enabling P synchronous ventricular pacing without adding to the complexity of implantation.

Acceleration↗
PubMed1992

Clinical experience with an activity sensing DDDR pacemaker using an accelerometer sensor.

The rate adaptive characteristics and pacemaker mediated tachycardia protection algorithm of an accelerometer based DDDR pacemaker were evaluated in 11 patients with bradycardia (seven atrioventricular block, four sick sinus syndrome). Rate adaptive programming was effected by collecting the acceleration level during a 3-minute moderate exercise ("tailoring" of sensor). In comparison with an externally attached piezoelectric sensor, the accelerometer sensor showed lower rate changes during external tapping of the pacemaker (16 +/- 3 vs 29 +/- 4 ppm, P less than 0.02) and applied direct pressure (1 +/- 1 vs 40 +/- 3 beats/min, P less than 0.001) on the pacemaker. At nominal setting, the accelerometer sensor showed improved rate stability and higher rate response to jogging and standing, although responses to other daily activities and treadmill exercise were similar. Apart from changing the rate responsive slope, rate response could be improved by repeat "tailoring" of the sensor at a lower exercise level, resulting in better overall rate response characteristics. The ability of the rate monitoring software to collect acceleration levels for an activity and profile the projected rate response at different rate responsive settings allowed programming to be effected with the minimum amount of exercise testing. The pacemaker also discriminated atrial tachyarrhythmias from normal sinus response using the sensor to judge the appropriateness of the atrial rate, which correctly identified and prevented rapid ventricular tracking in two patients during atrial flutter/fibrillation.

Adult↗
PubMed1991

Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice.

Phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), and the newly synthesized 5-phenylpentyl isothiocyanate (PPeITC), 6-phenylhexyl isothiocyanate (PHITC), and 4-(3-pyridyl)butyl isothiocyanate (PyBITC) were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of A/J mice. Mice were administered isothiocyanates by gavage for 4 consecutive days at doses of 5, 1, or 0.2 mumol/day prior to administration of 10 mumol of NNK by i.p. injection. Mice were sacrificed 16 weeks after NNK administration and pulmonary adenomas were quantitated, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mumol/day but was not inhibitory at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC. While virtually no differences in inhibitory activity could be ascertained for PPITC, PBITC, and PPeITC, PHITC appeared to be the most potent tumor inhibitor of all of the compounds. At a dose of 0.2 mumol/day, PHITC pretreatment reduced tumor multiplicity by 85%. PyBITC, an analogue of both NNK and PBITC, was ineffective as an inhibitor. Using the same protocol, the compounds were found to have qualitatively similar inhibitory effects on NNK-induced DNA methylation when administered at 1 mumol/day. These results extend our previous findings that increased alkyl chain length enhances the inhibitory activity of an arylalkyl isothiocyanate toward NNK lung tumorigenesis and demonstrate the exceptional chemopreventive potentials of two new isothiocyanates, PPeITC and PHITC.

Animals↗
PubMed1991

Stereoselective formation of in vitro nucleic acid adducts by 2,3-epoxy-4-hydroxynonanal.

This paper describes the reactions of purine nucleosides and nucleic acids with 2,3-epoxy-4-hydroxynonanal. 2,3-Epoxy-4-hydroxynonanal was produced with tert-butyl hydroperoxide by epoxidation of trans-4-hydroxy-2-nonenal, a lipid peroxidation product. The epoxy aldehyde exists as a pair of diastereomers, I and II. Because these isomers could not be completely separated under the chromatographic conditions used, reactions were carried out with a mixture of known proportions of isomers I and II. Reaction of adenine nucleosides with the epoxy aldehyde yielded diastereomers A1 and A2, which structures were assigned on the basis of their spectroscopic data and by chemical synthesis as 1,N6-etheno adducts possessing a heptyl group at C8. These adducts were formed from isomers I and II in a stereoselective manner. Isomer I appeared to be responsible for the formation of A2, whereas isomer II favored the production of A1. Stereoselectivity of isomers I and II was also observed upon reaction with guanine nucleosides in the formation of adducts G1, G2, G3, G4, G5, and G6, G2, G3, G5, and G6 were unstable in base and could be converted quantitatively to G1. The structures of these adducts were reported (Sodum, R. S., and Chung, F-L. Chem. Res. Toxicol., 2: 23-28, 1989). G5 and G6 were the products formed predominantly from reactions in which isomer I was in excess, whereas G1 and G4 were the major products in reactions enriched with isomer II. Incubation of DNA with the epoxy aldehyde at 37 degrees and pH 7.0 yielded a modified DNA containing 1,N2-ethenodeoxyguanosine (G1) at levels of 10 pmol/mg DNA. Although G2, G3, G5, and G6 were not readily detected in this DNA hydrolysate, base conversion of fractions corresponding to these adducts to G1 indicated that the total yield of these adducts was equivalent to approximately 20% of that of G1. A1 and A2 were not found in this DNA. Contrary to the reactions with native DNA, reactions of single-stranded DNA resulted in the formation of primarily A1 and A2, with a total adduct level of 30 nmol/mg DNA. In this DNA, the yield of guanine adducts was relatively small, estimated at 0.73 nmol/mg DNA based on conversion to G1. RNA was extensively modified by the epoxy aldehyde, yielding both adenine and guanine nucleosides. The levels of adenine nucleoside adducts formed in RNA were greater than 50 nmol/mg RNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1991

Detection of acrolein and crotonaldehyde DNA adducts in cultured human cells and canine peripheral blood lymphocytes by 32P-postlabeling and nucleotide chromatography.

People are constantly being exposed to toxic and carcinogenic aldehydes. However, little is actually known about the mechanisms underlying the toxic and carcinogenic effects of these aldehydes on human cells. The DNA alkylating activities of two of the more toxic and environmentally prominent alpha,beta-unsaturated aldehydes, acrolein and crotonaldehyde, have been studied utilizing 32P-postlabeling and nucleotide chromatographic techniques. Several putative adducts were observed in DNAs isolated from acrolein- and crotonaldehyde-treated human fibroblasts. One of these acrolein-DNA adducts was tentatively identified as the cyclic 1,N2-hydroxypropanodeoxyguanosine product, 3-(2'-deoxyribosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2- a]purine-10-one, by co-chromatography with a chemical standard. The 1,N2-hydroxypropanodeoxyguanosine along with other possible adducts, was also found in DNA isolated from peripheral blood lymphocytes obtained from a dog 1 h after receiving a therapeutic dose of 6.6 mg/kg of cyclophosphamide. These results not only demonstrate the presence of acrolein and crotonaldehyde DNA adducts in treated human cells, but also suggest that these sensitive techniques may be useful to the study of the importance of acrolein to both the carcinogenic and antineoplastic activities of cyclophosphamide and other oxazaphosphorine mustards.

Acrolein↗
PubMed1991

Nicotine-derived N-nitrosamines (TSNA) and their relevance in tobacco carcinogenesis.

Biochemical studies and bioassays support the concept that the increased risk for cancer of the oral cavity in snuff dippers and cancer of the lung, upper aerodigestive tract, and pancreas in smokers is most likely associated with the exposure to tobacco-specific N-nitrosamines. The doses of TSNA required to induce tumors in the oral cavity in rats and tumors in the lungs of rats and hamsters are comparable to the total doses of TSNA to which a long-term snuff dipper, respectively a cigarette smoker, are exposed over 4 decades. The carcinogenic NNN and NNK are metabolized to highly reactive electrophiles which react with nucleophilic centers of DNA and with proteins. The DNA-adducts are known to cause miscoding which can activate K-ras proto-oncogenes. K-ras oncogenes have been detected in adenocarcinomas of the lung of smokers. TSNA also form globin adducts in the blood of laboratory animals as well as of snuff dippers and smokers. Such adducts are currently being evaluated for their significance as biochemical markers of exposure to TSNA. These biomarkers may also serve as indicators for the possible endogenous formation of TSNA in tobacco chewers and smokers. Additional research needs in TSNA carcinogenesis include the development of modified methods for the reduction of TSNA in tobacco and smoke, inhibition of TSNA carcinogenesis by nutrients and micro-nutrients and the testing of chemopreventive agents.

Animals↗
PubMed1991

Inhibition of tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) tumorigenesis with aromatic isothiocyanates.

4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogenic nitrosamine. At low doses, it induces primarily lung tumours in mice, hamsters and rats, regardless of the route of administration. Its unique organ specificity and potency suggest its possible role in the high incidence of lung cancer in smokers. The goal of this study was to find agents that would potentially prevent NNK tumorigenesis. Previous results led us to test phenethyl isothiocyanate (PEITC) on NNK tumorigenesis in a two-year bioassay in Fischer 344 rats. The NNK-treated group developed 80% lung tumour incidence, whereas NNK-treated rats fed PEITC diets had only 40% lung tumour incidence. Incidences in other organs were not affected by this treatment. We also tested PEITC in a 16-week, short-term bioassay against NNK-induced lung adenomas in A/J mice. Pretreatment of mice with PEITC by gavage at four daily doses of 5 mumol or 25 mumol reduced the formation of NNK-induced lung adenomas by 70% or 100%, respectively. Interestingly, benzyl isothiocyanate and phenyl isothiocyanate, the lower homologues of PEITC, were inactive in this bioassay. Using a protocol similar to that used in the bioassays, PEITC was shown to decrease DNA methylation by NNK in the lungs of rats and mice and suppress the metabolism of NNK by mouse lung microsomes. These results are consistent with the previous data, suggesting that the inhibition of NNK-induced lung tumour formation by PEITC is a consequence of reduced DNA methylation caused by inhibition of NNK metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes and its inhibition by isothiocyanates.

The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung tumors in rats, mice, and hamsters, and metabolic activation is required for the carcinogenicity. 2-Phenethyl isothiocyanate (PEITC), whose precursor gluconasturtiin (a glucosinolate) occurs in cruciferous vegetables, has been found to inhibit carcinogenesis by NNK. The purpose of the study was to investigate the enzymes involved in the metabolism of NNK in lung microsomes and to elucidate the mechanisms of inhibition of NNK metabolism by isothiocyanates. NNK metabolism in lung microsomes (isolated from female A/J mice) resulted in the formation of formaldehyde, 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), 4-oxo-4-(3-pyridyl)butyric acid (keto acid), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone, and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol, displaying apparent Km values of 5.6, 5.6, 9.2, 4.7, and 2540 microM, respectively. Higher Km values in the formation of formaldehyde and keto alcohol were also observed. When cytochrome P-450 inhibitors [2-(diethylamino)ethyl 2,2-diphenylpentenoate] hydrochloride (100 microM), carbon monoxide (90%), and 9-hydroxyellipticine (10 microM) were used, NNK metabolism was inhibited by each 70, 100, and 30%, respectively. Methimazole (1 mM), an inhibitor of the flavin-dependent monooxygenase, inhibited the formation of 4-(methyl-nitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol by 20%, but had no effect on the formation of keto alcohol. Inhibitory antibodies against cytochromes P-450IIB1 and -2, P-450IA1, and P-450IA2 inhibited the formation of keto alcohol by 25, 15, and 0%, respectively. Administration of PEITC at doses of 5 and 25 mumol/mouse 2 h before sacrifice produced a 40 and 70% decrease in microsomal NNK metabolism, respectively. PEITC and 3-phenylpropyl isothiocyanate exhibited a mixed type of inhibition, and the competitive component of inhibition had apparent Ki values of 90 and 30 nM, respectively. Preincubation of PEITC in the presence of a NADPH-generating system did not result in a further decrease in the formation of NNK metabolites, indicating that the metabolism of PEITC was not required for the inhibition. When a series of isothiocyanates with varying alkyl chain length (phenyl isothiocyanate, benzyl isothiocyanate, PEITC, 3-phenylpropyl isothiocyanate, and 4-phenylbutyl isothiocyanate) were used, the potency of the inhibition increased with the increase in chain length.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗