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PubMedDate not supplied

In vitro metabolism of phenylacetone, phenyl-2-butanone, and 3-methyl-1-phenyl-2-butanone by rabbit liver preparations.

Phenylacetone, phenyl-2-butanone, and 3-methyl-1-phenyl-2-butanone were incubated with rabbit liver 9000g supernatant fraction for 30 and 60 min to yield primarily the alcohols, plus small amounts of 1,2-glycols and ketols (2-one-1-ols). Phenylacetone incubations produced small amounts of benzoic acid, which was confirmed as a true metabolite by incubation of 2H5 (phenyl-labeled) phenylacetone and corresponding recovery of phenyl-labeled benzoic acid. No benzoic acid was detectable from incubations of phenyl-2-butanone and 3-methyl-1-phenyl-2-butanone. 3-Methyl-1-phenyl-2-butanone yielded eight metabolites in addition to the corresponding alcohol, and structures are proposed for some of these metabolic products.

Acetone↗
PubMed1979

Potentiation of CCl4 hepatotoxicity in rats by a metabolite of 2-butanone: 2,3-butanediol.

The role of ketaone metabolism in 2-butanone-induced potentiaion of carbon tetrachloride (CCl4) hepatotoxicity was studied in rats. The blood concentrations of 2-butanol, 3-hydroxy-2-butanone and 2,3-butanediol detected 4 h after dosing were 3.2 mg/100 ml, 2.4 mg/100 ml and 8.6 mg/100 ml, respectively. Eighteen hours after 2-butanone, the concentration of 2,3-butanediol rose to 25.6 mg/100 ml, while the concentrations of 2-butanol and 3-hydroxy-2-butanone declined to 0.6 mg/100 ml and 1.4 mg/100 ml, respectively. A 16-h pretreatment with either 2-butanone (2.1 ml/kg, p.o.) or 2,3-butanediol (2.12 ml/kg, p.o.) markedly enhanced the hepatotoxic response to CCl4 (0.1 ml/kg, i.p.), as measured by serum glutamic pyruvic transaminase activity and hepatic triglyceride content. In vivo, limited formation of 3-hydroxy-2-butanone occurred after this dose of 2,3-butanediol. These data suggest that the production of 3-hydroxy-2-butanone and 2,3-butanediol via 2-butanone metabolism may participate in the augmented necrogenic effect of CCl4 seen after pretreatment with 2-butanone.

Alanine Transaminase↗
PubMedDate not supplied

Solvolysis of model compounds for alpha-hydroxylation of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: evidence for a cyclic oxonium ion intermediate in the alkylation of nucleophiles.

N'-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two potent tobacco-specific carcinogens, have been previously found to pyridyloxobutylate DNA. The adducts were found to be unstable and have not been fully characterized. In order to gain an understanding of the chemistry of the pyridyloxobutylating species, five model pyridyloxobutylating agents have been solvolyzed and the products identified. 4-[(Acetoxymethyl)-nitrosamino]-1-(3-pyridyl)-1-butanone (3), 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (4), 4-oxo-4-(3-pyridyl)-1-butyl p-toluenesulfonate (16), 2-chloro-2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (17), and 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanol (20) were solvolyzed in buffer and in buffer containing 20% MeOH. The solvolyses of 16 and 17 in H2O produced only 4-hydroxy-1-(3-pyridyl)-1-butanone (7). In the presence of 20% MeOH, 7 and 2-methoxy-2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (12) were produced from 16 and 17 in a 4:1 ratio. The solvolysis of 3 and 4 in the presence of esterase gave similar products. 4-Methoxy-1-(3-pyridyl)-1-butanone (8) was not detected as a product. In the absence of MeOH, compound 7, 3-pyridyl cyclopropyl ketone (10), and 1-(3-pyridyl)-but-2-en-1-one (18) were observed. In the presence of MeOH, 12 was also formed and the ratio of 7 to 12 was again about 4:1. The esterase-catalyzed hydrolysis of 20 yielded 1-(3-pyridyl)-1,4-butanediol (22), 1-(3-pyridyl)-1,3-butanediol (27), 1-(3-pyridyl)-but-3-en-1-ol (25), 1-(3-pyridyl)but-2-en-1-ol (26), and 2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (24).(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1976

The participation of 2-butanone in 2-butanol-induced potentiation of carbon tetrachloride hepatotoxicity.

The role of alcohol metabolism in 2-butanol-induced potentiation of carbon tetrachloride (CCl4) hepatotoxicity was studied in rats. Animals were sacrificed at various times after the administration of 2-butanol (2.2 ml/kg p.o.) for the determination of blood 2-butanol and 2-butanone concentrations by gas chromatographic analysis. 2-butanol exhibited an apparent elimination half-life of 2.5 hours. With the decline of 2-butanol concentrations, there was a rise in 2-butanone blood concentrations with 43 mg/100 ml detected at 1 hour and a maximum of 105 mg/100 ml detected 4 hours after the administration of the alcohol. A 16-hour pretreatment with either 2-butanol (2.2 ml/kg p.o.) or 2-butanone (1.87 ml/kg p.o.) markedly enhanced the hepatotoxic response of CCl4 (0.1 ml/kg i.p.) as measured by serum glutamic pyruvic transaminase activity, hepatic glucose-6-phosphatase activity and triglyceride content. The enhanced hepatotoxicity produced by 2-butanol was not significantly different from that produced by 2-butanone. The potentiation of CCl4 hepatotoxicity by both agents was substantiated morphologically. The results indicate that 2-butanone production via the oxidation of 2-butanol appears to contribute to the marked response of 2-butanol.

Alanine Transaminase↗
PubMed1992

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by inducible and constitutive cytochrome P450 enzymes in rats.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces tumor formation in the liver, lung, nasal cavity, and pancreas of rats. Metabolic activation is required for the tumorigenicity of this compound. The involvement of cytochrome P450 enzymes in NNK bioactivation was investigated in rats by studies with chemical inducers and antibodies against P450s. Liver microsomal enzymes catalyzed the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde), 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) from NNK. When the activity was expressed on a per nanomole P450 basis, treatments of rats with 3-methylcholanthrene (MC), phenobarbital (PB), pregnenolone 16-alpha-carbonitrile (PCN), Aroclor 1254 (AR), safrole (SA), and isosafrole (ISA) increased the keto aldehyde formation in liver microsomes 2.0-, 2.4-, 3.8-, 2.5-, 2.1-, and 1.8-fold, respectively; PB, AR, SA, and ISA increased the keto alcohol formation 1.7-, 1.3-, 2.0-, and 1.3-fold, respectively. The extents of induction were more pronounced when expressed on a per milligram protein basis, due to the higher microsomal P450 contents in the induced microsomes. The formation of NNK-N-oxide was markedly increased by PB and PCN and slightly increased by AR, SA, and ISA. However, the formation of NNAL, the major metabolite due to carbonyl reduction, was not increased by the treatments but was decreased by AR, ISA, and acetone (AC). The kinetic parameters of NNK metabolism by control, MC-, PB-, and PCN-induced liver microsomes were obtained. A panel of monoclonal (anti-1A1, -2B1, -2C11, and -2E1) and polyclonal (anti-1A2, -2A1, and -3A) antibodies were used to assess the involvement of constitutive hepatic P450 enzymes in NNK metabolism. Keto aldehyde formation was inhibited by anti-1A2 and anti-3A (about 15%) but not by others; the formation of keto alcohol was inhibited by anti-1A2, anti-2A1, and anti-3A (by 13-26%). In incubations with lung microsomes, the formation of keto aldehyde, keto alcohol, NNK-N-oxide, and NNAL were observed. With nasal mucosa microsomes, however, only keto aldehyde and keto alcohol formation were appreciable. SA and AC significantly decreased NNK metabolism in lung and nasal mucosa microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Biosynthesis of riboflavin: cloning, sequencing, and expression of the gene coding for 3,4-dihydroxy-2-butanone 4-phosphate synthase of Escherichia coli.

3,4-Dihydroxy-2-butanone 4-phosphate is biosynthesized from ribulose 5-phosphate and serves as the biosynthetic precursor for the xylene ring of riboflavin. The gene coding for 3,4-dihydroxy-2-butanone 4-phosphate synthase of Escherichia coli has been cloned and sequenced. The gene codes for a protein of 217 amino acid residues with a calculated molecular mass of 23,349.6 Da. The enzyme was purified to near homogeneity from a recombinant E. coli strain and had a specific activity of 1,700 nmol mg-1 h-1. The N-terminal amino acid sequence and the amino acid composition of the protein were in agreement with the deduced sequence. The molecular mass as determined by ion spray mass spectrometry was 23,351 +/- 2 Da, which is in agreement with the predicted mass. The previously reported loci htrP, "luxH-like," and ribB at 66 min of the E. coli chromosome are all identical to the gene coding for 3,4-dihydroxy-2-butanone 4-phosphate synthase, but their role had not been hitherto determined. Sequence homology indicates that gene luxH of Vibrio harveyi and the central open reading frame of the Bacillus subtilis riboflavin operon code for 3,4-dihydroxy-2-butanone 4-phosphate synthase.

Amino Acid Sequence↗
PubMed1992

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human lung and liver microsomes and cytochromes P-450 expressed in hepatoma cells.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-specific carcinogen in animals, has been linked to tobacco-related cancers in humans. The cytochrome(s) P-450 (P-450) responsible for the metabolic activation of NNK in humans has not been identified. The present work investigated the ability of human lung and liver microsomes and 12 forms of human P-450, expressed in Hep G2 (hepatoma) cells, to metabolize NNK. Of the 12 P-450 forms, P-450 1A2 had the highest activity in catalyzing the conversion of NNK to the keto alcohol, 4-hydroxy-1-(3-pyridyl)-1-butanone. P-450s 2A6, 2B7, 2E1, 2F1, and 3A5 also had measurable activities in the formation of keto alcohol. The apparent Km and Vmax for the formation of keto alcohol in the P-450 1A2-expressed Hep G2 cell lysate were 309 microM and 55 pmol/min/mg protein, respectively. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, a reductive product, was the major metabolite formed, whereas the formation of keto alcohol and its aldehyde and acid derivatives (all alpha-hydroxylation products) constituted approximately 1% of the initial amount of NNK in P450-expressed Hep G2 cell lysate. A similar metabolite pattern was observed with human lung or liver microsomes. In human lung microsomes, the apparent Kms for the formation of 4-hydroxy-4-(3-pyridyl)butyric acid, 4-oxo-1-(3-pyridyl)-1-butanone, NNK-N-oxide, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were 526, 653, 531, and 573 microM, respectively; the formation of keto alcohol was not observed. For human lung microsomes, there was no sex-related difference in NNK metabolism. Carbon monoxide (90% atmosphere) significantly inhibited the metabolism of NNK in human lung and liver microsomes. 7,8-Benzoflavone, an inhibitor of P-450s 1A1 and 1A2, had no effect on NNK metabolism in human lung microsomes but decreased the formation of keto alcohol by 47% in human liver microsomes. Similarly, antibodies against human P-450s 1A2 and 2E1 decreased keto alcohol formation by 42% and 53%, respectively, in human liver microsomes but did not affect NNK metabolism in lung microsomes. Inhibitory antibodies against P-450s 2A1, 2C8, 2D1, or 3A4 had little or no effect on the metabolism of NNK in human liver or lung microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1991

Quantitation of microsomal alpha-hydroxylation of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is activated to DNA alkylating species via two different alpha-hydroxylation pathways. Methylene hydroxylation leads to DNA methylation, whereas methyl hydroxylation yields DNA pyridyloxobutylation. We have developed a high-pressure liquid chromatography assay utilizing radiochemical detection that permits the determination of the extent of metabolism through each pathway in microsomal preparations. Levels of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) were used to measure the extent of methyl hydroxylation, whereas levels of the aldehyde, 4-oxo-1-(3-pyridyl)-1-butanone (OPB), were used to quantify the extent of methylene hydroxylation. Incubations of [5-3H]NNK with microsomes and cofactors were conducted in the presence of 5 mM sodium bisulfite to trap the reactive OPB. The inclusion of bisulfite did not affect the rate of NNK metabolism. Trapping the aldehyde also inhibited its further oxidation to the corresponding acid or reduction to HPB. Furthermore, the conversion of HPB to OPB made only a minor contribution to the OPB levels under our incubation conditions. Analysis of incubation mixtures containing [5-3H]NNK, cofactors, and either A/J mouse liver or lung microsomes demonstrated that OPB was a significant metabolite of NNK. The OPB:HPB ratio was greater in liver (1.5) than in lung (0.2-1) microsomal preparations. Apparent Km values for OPB and HPB formation in lung microsomes were 23.7 and 3.6 microM, respectively, whereas the corresponding values for liver microsomes were 19.1 and 73.8 microM, respectively. These data are consistent with the involvement of more than one cytochrome P-450 isozyme in the activation of NNK to DNA reactive species.

Animals↗
PubMed1978

Psychotropic agents. 3. 4-(4-Substituted piperidinyl)-1-(4-fluorophenyl)-1-butanones with potent neuroleptic activity.

A series of 1-(4-fluorophenyl)-4-(1-piperidinyl)-1-butanones substituted with benzimidazole, benzotriazole, or quinoxaline at the 4 position of the piperidine ring was synthesized and subjected to neuroleptic tests. Neuroleptic activities of several compounds were comparable to those of haloperidol. In particular, 4-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone (10) was characterized by having a potent neuroleptic activity with less liability to the extrapyramidal side effect.

Animals↗
PubMed1990

Field studies on the potential of butanone, carbon dioxide, honey extract, 1-octen-3-ol, L-lactic acid and phenols as attractants for mosquitoes.

Various combinations of six candidate attractants--butanone, carbon dioxide (CO2), honey, octenol, lactic acid and mixed phenols--were tested against natural populations of mosquitoes in Everglades National Park, Florida, U.S.A., using unlighted CDC-baited traps. With few exceptions, the attractancy of these candidate compounds to mosquitoes, when used alone, was less than that of CO2 alone. The exceptions were that octenol and honey extract alone attracted larger numbers of Coquillettidia perturbans (Walker). Addition of lactic acid and/or octenol to CO2 increased trap collections of Aedes taeniorhynchus (Wiedemann), Anopheles atropos D. & K., and An. crucians Wiedemann by 1.4-13.8 times. Culex nigripalpus Theobald collections were increased 2.7 times by the addition of lactic acid, while the addition of octenol produced mixed results. Whereas the addition of lactic acid reduced collections of Cx (Melanoconion) spp., the addition of octenol generally increased collections. The opposite happened for Wyeomyia mitchellii (Theobald). For the biting midge, Culicoides furens (poey), octenol (1.6-23.4 x ) and phenol (2.7 x ) alone attracted larger numbers, and lactic acid alone attracted approximately the same numbers as CO2 alone. The combinations octenol + phenol and octenol + 200 ml/min CO2 increased C. furens collections c. 100 times over CO2 alone. The combination of octenol + CO2 increased (1.6 x ) collections of the tabanid Diachlorus ferrugatus (Fabricius). Butanone appeared to decrease the trap collections of all species when combined with CO2 or octenol + CO2.

Animals↗
PubMed1992

Analysis of mutagenic activity and ability to induce replication of polyoma DNA sequences by different model metabolites of the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) requires metabolic activation to express its carcinogenic activity. This activation leads to the formation of methylating and pyridyloxobutylating agents. To determine the possible biological effects mediated by each of these metabolic pathways we have studied the activities of model compounds that are metabolized to either a methylating or pyridyloxobutylating species. Each model compound was evaluated for its mutagenic activity in both prokaryotic and eukaryotic cell systems. The model compounds were also tested for their ability to induce asynchronous replication of viral DNA sequences. We demonstrate here that both the methylating model compound acetoxymethylmethylnitrosamine (AMMN) and the pyridyloxobutylating model compound 4-(acetoxymethyl)-1-(3-pyridyl)-1-butanone (NNKOAc) were mutagenic in strains TA98, TA100, and TA1535 but not TA102. While NNKOAc appeared to be 10 times more potent than AMMN in Salmonella, AMMN was found to be a more potent mutagen in mammalian G12 cells. Both chemicals could induce asynchronous replication of polyoma DNA sequences in rat fibroblast cells carrying an integrated copy of the polyoma virus with AMMN appearing to be more active. Measurement of DNA adduct levels suggest that the damage produced by NNKOAc was at least as active as that produced by AMMN when viewed on a per adduct basis. The possible implications of the biological activities exhibited by methylating and pyridyloxobutylating model compounds to NNK induced carcinogenesis are discussed.

Animals↗
PubMedDate not supplied

Evidence that a hemoglobin adduct of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a 4-(3-pyridyl)-4-oxobutyl carboxylic acid ester.

Hemoglobin adducts of the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) upon mild base or acid hydrolysis. HPB has been detected in hydrolysates of human hemoglobin and has been proposed as a dosimeter of exposure to and metabolic activation of NNK in people exposed to tobacco products. In this study, labeling experiments were carried out with Na18OH which provide strong evidence that the globin adduct which releases HPB upon base hydrolysis is a carboxylic acid ester. Globin was isolated from rats treated with NNK. This globin was reacted with NaCNBH3, followed by hydrolysis at room temperature with 0.2 N NaOH. Analysis of the products demonstrated the presence of 4-hydroxy-1-(3-pyridyl)-1-butanol (7), but not HPB. These results demonstrate that the adduct in globin has a free carbonyl group and is not a Schiff base. This sequence of reactions was then carried out with Na18OH, under conditions which would have resulted in incorporation of 18O into 7 if nucleophilic displacement at carbon 4 of the adduct had occurred. Analysis of the products by GC-MS showed no detectable incorporation of 18O into 7. These results demonstrate that the globin adduct which releases HPB upon base hydrolysis is a 4-(3-pyridyl)-4-oxobutyl carboxylic ester. Consistent with this conclusion, a model ester, alpha-methyl beta-[4-(3-pyridyl)-4-oxobutyl] N-(carbobenzyloxy)-L-aspartate (13), hydrolyzed in base and acid in a manner similar to that observed with globin from NNK-treated rats.

Animals↗
PubMed1991

In vivo and in vitro persistence of pyridyloxobutyl DNA adducts from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The persistence of pyridyloxobutyl DNA adducts in lung and liver of F-344 rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated. The levels of these adducts were determined at various time points up to 4 weeks post s.c. injection of [5-3H]NNK (0.8 mg/kg body wt). Maximal levels of the adducts were observed between 4 and 24 h in both tissues. The disappearance of the adducts from lung and liver DNA was multiphasic with initial half-lives of 50 and 38 h respectively. In both cases, detectable levels of the pyridyloxobutyl adducts were observed at 4 weeks post injection. The in vitro rate of adduct disappearance was studied using calf thymus DNA reacted with 4-(acetoxymethylnitrosamino)-1-(3-[5-3H]pyridyl)-1-butanone in the presence of esterase. Adduct levels were measured for up to 2 weeks after the initiation of the experiment. The decomposition of these adducts was triphasic with half-lives of 6, 120 and 430 h. The multiphasic disappearance of the pyridyloxobutyl adducts suggests that there is more than a single adduct generated upon pyridyloxobutylation of DNA and that at least one of these adducts has a significant lifetime in DNA.

Animals↗
PubMed1991

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytochrome P450IIB1 in a reconstituted system.

Several previous studies have suggested that cytochrome P450IIB1 is involved in the bioactivation of the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in rats as well as in mouse lung microsomes. The present investigation was undertaken to study the metabolism of NNK by purified cytochrome P450IIB1 in a reconstituted system. The metabolites 4-hydroxy-4-(3-pyridyl) butyric acid (hydroxy acid), 4-oxo-4-(3-pyridyl) butyric acid (keto acid), 4-oxo-4-(3-pyridyl) butanol (keto aldehyde), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide) and 4-oxo-4-(3-pyridyl)-1-butanol (keto alcohol) were quantitated by HPLC. The results showed that, in addition to alpha-hydroxylations, cytochrome P450IIB1 also catalyzed the formation of NNK-N-oxide efficiently, and to a certain extent, the conversion of NNK primary hydroxylation metabolites (keto aldehyde and keto alcohol) to secondary metabolites (keto acid and hydroxy acid). Cytochrome b5 at a ratio of 1:1 or 2:1 to P450IIB1 had no significant effect on the metabolic activities and profiles of NNK. The apparent Km values for the formation of keto aldehyde, NNK-N-oxide and keto alcohol were respectively 191.2, 131.4 and 318.0 microM with corresponding apparent Vmax values of 89.7, 295.5 and 333.3 pmol/min/nmol P450, indicating that hydroxylation at the alpha-methyl position is preferred over the alpha-methylene position. Measurement of formaldehyde, a product derived from the alpha-methyl hydroxylation, was developed as a convenient method to study NNK metabolism. Thiourea activated cytochrome P450IIB1-catalyzed NNK metabolism significantly. Phenethyl isothiocyanate, an inhibitor of NNK-induced lung carcinogenesis, inhibited P450IIB1-catalyzed NNK demethylation in a concentration-dependent manner. This work demonstrates that purified P450IIB1 can catalyze the conversion of NNK to most of its oxidative metabolites.

Animals↗
PubMed1991

Effect of phenethyl isothiocyanate on the metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by cultured rat lung tissue.

The effect of phenethyl isothiocyanate (PEITC), a dietary inhibitor of carcinogenesis, on the metabolism of the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cultured rat peripheral lung tissues was investigated. Initially, the metabolism of NNK by the tissues was studied by incubating the lung explants in medium containing 1 and 10 microM [5-3H]NNK for 3, 6, 12, and 24 h. NNK metabolites were analyzed and quantified by HPLC and expressed as nmol/mg DNA. NNK was metabolized by three pathways; alpha-carbon hydroxylation, pyridine N-oxidation and carbonyl reduction. The principal metabolic pathway involved the conversion of NNK to the pyridine N-oxidized metabolites: 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide) and 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol (NNAL-N-oxide). When combined, NNK-N-oxide and NNAL-N-oxide constituted approximately 70% of the total metabolites in the medium at 24 h. To determine the effects of PEITC on the metabolism of NNK, lung explants were either treated with both 10 microM [5-3H]NNK and PEITC (10, 50, and 100 microM) for 24 h, or they were pre-treated with these same concentrations of PEITC for 16 h and then co-treated with both PEITC and 10 microM [5-3H]NNK for 24 h. In both treatment series, PEITC inhibited the alpha-carbon hydroxylation and pyridine N-oxidation of NNK and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is produced from NNK by carbonyl reduction. In general, the inhibition of NNK metabolism was greater when the explants were pre-treated with PEITC. These results suggest that PEITC is an effective inhibitor of the conversion of NNK to metabolites that elicit DNA damage. Our results are in agreement with previously published data in which PEITC was shown to inhibit NNK metabolism and tumorigenesis in the rat lung.

Animals↗
PubMed1991

Quantification of 4-hydroxy-1-(3-pyridyl)-1-butanone released from human haemoglobin as a dosimeter for exposure to tobacco-specific nitrosamines.

A method was developed to quantify globin adducts of the tobacco-specific nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). Globin adducts of NNK and NNN release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) after mild treatment with a base. HPB was analysed as its pentafluorobenzoate by capillary column gas chromatography with detection by negative-ion chemical ionization-mass spectrometry and selected-ion monitoring. The detection limit for HPB-pentafluorobenzoate was approximately 1 fmol/injection. The method was applied to haemoglobin from snuff dippers, smokers and nonsmokers. Adduct levels were highest in snuff dippers (517 +/- 538 fmol HPB per gram haemoglobin), followed by smokers (79 +/- 189 fmol HPB per gram haemoglobin) and nonsmokers (29.3 +/- 25.9 fmol HPB per gram haemoglobin). The method will be useful in assessing the role of tobacco-specific nitrosamines as causes of cancer in smokers and snuff dippers.

Environmental Monitoring↗
PubMed1991

O6-methylguanine is a critical determinant of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone tumorigenesis in A/J mouse lung.

The relative importance of the two alpha-hydroxylation pathways in the tumorigenicity of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was examined in the A/J mouse lung. Methyl hydroxylation, which results in DNA pyridyloxobutylation, was investigated with 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) and N'-nitrosonornicotine. Methylene hydroxylation, which leads to DNA methylation, was studied by using acetoxymethyl-methylnitrosamine (AMMN). The tumorigenic activities of these compounds were compared to that of 10 mumol NNK at doses that yielded similar or greater adduct levels 24 h after exposure. The methylating agent AMMN was more tumorigenic than the pyridyloxobutylating agents, NNKOAc and N'-nitrosonornicotine. NNKOAc enhanced the tumorigenic activity of AMMN when the two compounds were given in combination. These results suggested that DNA methylation was more important than DNA pyridyloxobutylation in A/J mouse lung tumor induction by NNK and that pyridyloxobutylation enhanced the activity of the methylation pathway. However, the tumorigenicity of 10 mumol NNK could not be reproduced by AMMN +/- NNKOAc at doses that yielded similar levels of DNA adducts 24 h after exposure. Therefore, a second study was conducted in which the persistence of O6-methylguanine in lung DNA following various doses of NNK or AMMN +/- NNKOAc was compared to the tumorigenicity of these treatments. A strong correlation was observed between lung tumor yield and levels of O6-methylguanine at 96 h for NNK and AMMN +/- NNKOAc (r = 0.98). The ability of NNKOAc to increase the tumorigenic activity of AMMN was attributed to its ability to enhance the persistence of O6-methylguanine in lung DNA. These results demonstrate that the formation and persistence of O6-methylguanine are critical events in the initiation of A/J mouse lung tumors by NNK. They also suggest that DNA pyridyloxobutylation by NNK can increase the persistence of this promutagenic base in lung DNA.

Animals↗