Synthesis of anti-1,2-dihydroxy-3,4-epoxy-1,2,3, 4-tetrahydro-6-nitrochrysene and its reaction with 2'-deoxyguanosine- 5'-monophosphate, 2'-deoxyadenosine-5'-monophosphate, and calf thymus DNA in vitro.

The remarkable carcinogenic activity of 6-nitrochrysene (6-NC) in several animal models, and its environmental presence, suggest its potential importance with regard to human cancer development. Depending on the bioassay model, 6-NC can be activated by simple nitro reduction, ring oxidation, or by a combination of ring oxidation and nitro reduction. Only the first pathway has been clearly established.

Synthesis of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene and its reaction with DNA.

Substitution of a methyl group in the bay region can enhance the tumorigenicity of polycyclic aromatic hydrocarbons such as chrysene, benz[a]anthracene, and others. This phenomenon has been related to facile DNA adduct formation of bay region diol epoxides with a methyl group and epoxide ring in the same bay. While anti-7, 8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its DNA adduct formation have been studied extensively, it is not known whether a methyl substituent in the bay region alters the reactivity of DNA in this system.

Inhibition of lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen: caffeine as an important constituent.

Here, we examined the effect of black tea and caffeine on lung tumorigenesis in F344 rats induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in a 2-year bioassay. NNK was administered s.c.

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human hepatic microsomes by ipomeanol analogs--an exploratory study.

The tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen in mice, rats and Syrian golden hamsters and a suspected human lung carcinogen. We have reported earlier that structural analogs of the naturally occurring pulmonary toxin 4-ipomeanol (IPO) were non toxic up to 50 micromol/mouse. Because these analogs are in part structurally similar to NNK, they are expected to compete for the same enzymes and/or reactive sites within DNA.

Inhibition of N-nitrosodimethylamine demethylase in rat and human liver microsomes by isothiocyanates and their glutathione, L-cysteine, and N-acetyl-L-cysteine conjugates.

Natural and synthetic isothiocyanates and their conjugates were examined for their inhibitory effects toward rat and human liver microsomal N-dimethylnitrosoamine demethylase (NDMAd) activity using a radiometric NDMAd assay. Substrate concentrations of 30 and 60 microM were used to probe the activity of cytochrome P4502E1 isozyme through the alpha-hydroxylation of NDMA. It was found that alkyl isothiocyanates such as sulforaphane and allyl isothiocyanate displayed very weak inhibition, whereas the arylalkyl isothiocyanates such as benzyl and phenethyl isothiocyanate showed significant inhibition toward rat liver NDMAd activity with IC50 values of 9.

The essential role of the functional group in alkyl isothiocyanates for inhibition of tobacco nitrosamine-induced lung tumorigenesis.

The importance of the isothiocyanate group in alkyl isothiocyanate for inhibition of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)-induce lung tumorigenesis was examined in A/J mice. Our previous structure-activity relationship study of isothiocyanates showed that 1-dodecyl isothiocyanate [CH3(CH2)11NCS], a simple alkyl isothiocyanate, is a potent inhibitor of NNK-induced lung tumorigenesis. It was chosen for this study due to its structural features and potency.

Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats.

The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.

Scientific challenges in environmental carcinogenesis.

We reviewed three of our ongoing interdisciplinary studies in environmental carcinogenesis. In the case of snuff dipping and cancer of the oral cavity our data strongly support the epidemiological findings. Bioassays have demonstrated that oral snuff induces cancer of the oral cavity of rats, that the major carcinogens in snuff are NNN and NNK and that swabbing of the mouth with a solution containing NNN and NNK induces tumors in rats at the site of application.

Assessment of major carcinogenic tobacco-specific N-nitrosamines in Thai cigarettes.

This report presents new findings on the content of cancer-causing tobacco-specific N-nitrosamines (TSNA) in mainstream smoke of nine brands of commercially produced Thai cigarettes, representing about 85% of market share in Thailand. Also tested were two major and popular brands of U.S.

The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung.

In the U.S., there has been a steeper rise of the incidence of lung adenocarcinoma than of squamous cell carcinoma of the lung among cigarette smokers.

Formation and analysis of tobacco-specific N-nitrosamines.

Chemical-analytical studies during the past 4 years led to several new observations on the formation of tobacco-specific N-nitrosamines (TSNA) and their occurrence in smokeless tobacco, mainstream smoke (MS), and sidestream smoke (SS) of American and foreign cigarettes. When snuff was extracted by means of supercritical fluid extraction with carbon dioxide containing 10% methanol, analysis of this material confirmed that the extraction with organic solvents had been partially incomplete. Epidemiological studies in the northern Sudan showed a high risk for oral cancer for users of toombak, a home-made oral snuff.

Ipomeanol analogs as chemopreventive agents: effect on the in vitro metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific, powerful, organospecific lung carcinogen. 4-Ipomeanol (IPO) is an investigational chemotherapeutic drug with specific toxicity towards the lung. We hypothesized that non-toxic analogs of IPO could be competitive inhibitors of the metabolic activation of NNK.

Chemoprevention by isothiocyanates.

Naturally occurring and synthetic isothiocyanates are among the most effective chemopreventive agents known. A wide variety of isothiocyanates prevents cancer in the rat lung, mammary gland, esophagus, liver, small intestine, colon, and bladder. Mechanistic studies have shown that this chemopreventive activity is due to favorable modification of phase I and phase II carcinogen metabolism, resulting in increased carcinogen excretion or detoxification and decreased carcinogen DNA interactions.

Identification and quantification of the N-acetylcysteine conjugate of allyl isothiocyanate in human urine after ingestion of mustard.

Allyl isothiocyanate (AITC) is a constituent of cruciferous vegetables. It occurs widely in the human diet as a natural ingredient or food additive. AITC possesses numerous biochemical and physiological activities.

Structure-activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice.

A structure-activity relationship study was carried out to identify structural features in arylalkyl and alkyl isothiocyanates that are associated with the inhibitory potency of these compounds against lung tumorigenesis induced in A/J mice by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These features include the alkyl chain length, phenyl substitution, and secondary isothiocyanates. The naturally occurring allyl isothiocyanate, phenethyl isothiocyanate, and the synthetic analogues such as 6-phenylhexyl isothiocyanate, 8-phenyloctyl isothiocyanate, 10-phenyldecyl isothiocyanate, 1,2-diphenylethyl isothiocyanate, 2,2-diphenylethyl isothiocyanate, and alkyl isothiocyanates (with 1-hexyl, 2-hexyl, and 1-dodecyl as alkyl moieties) were assayed in mice for their tumor inhibitory potential.

A study of tobacco carcinogenesis. LI. Relative potencies of tobacco-specific N-nitrosamines as inducers of lung tumours in A/J mice.

Tobacco-specific N-nitrosamines (TSNA) are formed from nicotine and the minor Nicotiana tabacum alkaloids during tobacco processing and tobacco smoking. The TSNA are the most abundant strong carcinogens in smokeless tobacco and in smoke. In this comparative study six TSNA and two major volatile N-nitrosamines of cigarette smoke are assayed for their relative tumorigenicities in strain A/J female mice and for their potential to induce lung tumors.

Glycolytic enzymes as DNA binding proteins.

1. Numerous studies have demonstrated the presence of at least four glycolytic enzymes in the nuclear compartment of several cell systems. 2.

A study of tobacco carcinogenesis: effect of the fat content of the diet on the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.

3 Epidemiological studies indicate that the risk of cigarette smokers for cancer of the lung and of the pancreas is influenced by the fat content of the daily diet. In a long-term bioassay (24 months), we gave F344 rats 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific and strongly carcinogenic N-nitrosamine, as a 2 ppm solution in the drinking water. One group of rats was given a high-corn oil diet (23.

Effect of varying proportions of dietary menhaden and corn oil on experimental rat mammary tumor promotion.

Dose-related effects of long-chain highly unsaturated n-3 fatty acids on the development of N-nitrosomethylurea (NMU)-induced rat mammary tumors were assessed in female F344 rats. Four test groups (36 rats/group) were fed the following high-fat (HF) diets (23% fat, w/w): Group 1, 18% menhaden oil (MO) and 5% corn oil (CO); Group 2, 11% MO and 11.8% CO; Group 3, 5% MO and 18% CO; Group 4, CO alone.

Two types of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone hemoglobin adducts, from metabolites which migrate into or are formed in red blood cells.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), is considered to play an important role in the induction of lung cancer in tobacco users. In rats treated with [5-3H]NNK, 20 to 40% of the tritium bound to hemoglobin (Hb) is released by base hydrolysis as 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). This HPB-releasing adduct has been quantified in tobacco users and is considered a biochemical marker for uptake and activation of tobacco-specific nitrosamines.

Urinary trans,trans-muconic acid as an indicator of exposure to benzene in cigarette smokers.

Epidemiological studies have shown an association between cigarette smoking and increased risk of myeloid leukemia in smokers. In evaluating this link it is important to note that cigarette smoke contains benzene, among other carcinogens. Since chronic benzene, among other carcinogens.

Analysis of tobacco-specific N-nitrosamines in indoor air.

A method was developed and applied for the assessment of tobacco-specific N-nitrosamines (TSNA) in indoor air polluted with tobacco smoke. Air samples were collected on Cambridge filters treated with 0.01 M potassium bisulfate, extracted with dichloromethane and enriched by column chromatography.

Rat liver metabolism of benzo[b]naphtho[2,1-d]thiophene.

Thioarenes, sulfur-containing polycyclic aromatic hydrocarbons, have been detected in a number of environmental sources. The metabolism of one thioarene, benzo[b]naphtho[2,1,d]thiophene ([2,1]BNT), by F344 rat liver 9000g supernatant (S-9) was studied. [2,1]BNT which is structurally analogous and has similar carcinogenic potency to chrysene, was metabolized to six ethyl acetate-extractable metabolites when incubated with S-9 from Aroclor 1254-treated F344 rats.

Bioavailability of tobacco-specific N-nitrosamines to the snuff dipper.

Use of supercritical carbon dioxide extraction in the analysis of smokeless tobacco for tobacco-specific N-nitrosamines revealed the presence of higher levels of 4-(methylnitros-amino)-1-(3-pyridyl)-1-butanone (NNK) than had been determined with conventional methods. Whether human saliva may be similarly capable of releasing apparently bound NNK during chewing or snuff dipping was tested by incubating smokeless tobacco with enzymatically active saliva and with heat-treated saliva respectively. Enzymatically active human saliva was found to liberate up to twice the amount of the highly carcinogenic NNK than did heat-treated saliva.