Mechanisms of membrane toxicity of hydrocarbons.

Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.

Metabolism and Disposition Kinetics of Nicotine

Guidelines for Canadian Drinking Water Quality

A biomarker is desirable in quantitating systemic exposure both in smokers and nonsmokers to constituents of tobacco smoke. Self-report measures in smokers, such as cigarettes smoked per day, are highly imprecise owing to individual differences in how cigarettes are smoked, with ranges of nicotine intake per cigarette from 0.3 to 3.0 mg (1, 2). Self-report measures, such as hours per day exposed to environmental tobacco smoke (ETS) by nonsmokers, are also likely to be imprecise indicators of intake of tobacco smoke owing to variations in the number of cigarettes smoked, proximity of nonsmokers to smokers, room ventilation and other environmental characteristics, as well as individual differences in sensitivity to and/or concern about adverse effects of ETS. The optimal assessment of exposure to tobacco smoke would be by analysis of the concentrations of a component of smoke in the body fluids of an exposed individual— i.e., a biologic marker or biomarker. There are two broad questions that need to be considered in assessing the validity of a biomarker of tobacco smoke exposure. The first is how well does the concentration of a marker chemical in the air reflect exposure to toxic constituents of smoke that are of concern? The second is how well does a concentration of a particular chemical in a biologic fluid reflect an individual's intake of that chemical (or a related chemical) from tobacco smoke? The National Research Council (3) has proposed criteria for a valid marker of ETS in the air as follows: The marker 1) should be unique or nearly unique for ETS so that other sources are minor in comparison; 2) should be easily detectable; 3) should be emitted at similar rates for a variety of tobacco products; and 4)

Cotinine as a Biomarker of Environmental Tobacco Smoke Exposure

Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells.

Screening of tobacco smoke constituents for mutagenicity using the Ames' test.

Simultaneous determination of nicotine and cotinine in plasma using capillary column gas chromatography with nitrogen-sensitive detection

Cigarette smoke condensate is known to enhance the frequency of sister-chromatid exchanges (SCE) in human lymphocytes in vitro and some of the activity has been found in the most volatile part of the particulate phase, the semivolatile fraction. In this study we have investigated the chemical composition and the SCE-inducing activity of the weakly acidic, semivolatile fraction of a cigarette smoke condensate. A number of individual weakly acidic compounds were also tested for their SCE-inducing effects. The weakly acidic fraction was separated by preparative gel chromatography into 11 subfractions (F1-F11). The chemical composition was determined by gas chromatography and gas chromatography-mass spectrometry. Measurements of the effects on SCE in human lymphocytes were used to evaluate the genotoxic effects. All fractions except F11 induced SCE in a dose-dependent way. The most active fraction was F4 which contained mainly alkyl-2-hydroxy-2-cyclopenten-1-ones. The individual compounds to be tested for induction of SCE were selected on the basis of their abundance in the weakly acidic subfractions and on the basis of their occurrence in the environment. Of 23 tested compounds, most of which were alkylphenols, 7 induced SCE, i.e., catechol, 2-(1-propenyl)phenol, cyclotene, maltol, isoeugenol, 2-methoxyphenol (guaiacol) and vanillin. Many of these are important flavor components that occur not only in tobacco and tobacco smoke but also in food, candies, beverages and perfumes.

In vitro studies of biological effects of cigarette smoke condensate. II. Induction of sister-chromatid exchanges in human lymphocytes by weakly acidic, semivolatile constituents.

Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities of harm reduction within the tobacco area. Although current manufacturing methods for snus build on those that were introduced more than a century ago, the low levels of unwanted substances in modern Swedish snus are largely due to improvements in production techniques and selection of raw materials in combination with several programs for quality assurance and quality control. These measures have been successively introduced during the past 30-40 years. In the late 1990s they formed the basis for a voluntary quality standard for Swedish snus named GothiaTek ® . In recent years the standard has been accepted by the members of the trade organization European Smokeless Tobacco Council (ESTOC) so it has now evolved into an industrial standard for all smokeless tobacco products in Europe. The initial impetus for the mentioned changes of the production was quality problems related to microbial activity and formation of ammonia and nitrite in the finished products. Other contributing factors were that snus came under the jurisdiction of the Swedish Food Act in 1971, and concerns that emerged in the 1960s and 1970s about health effects of tobacco, and the significance of agrochemical residues and other potential toxicants in food stuffs. This paper summarizes the historical development of the manufacture of Swedish snus, describes the chemical composition of modern snus, and gives the background and rationale for the GothiaTek ® standard, including the selection of constituents for which the standard sets limits. The paper also discusses the potential future of this voluntary standard in relation to current discussions about tobacco harm reduction and regulatory science in tobacco control.

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Swedish snus and the GothiaTek® standard

The mechanism responsible for the modification of mutagenicity by chlorophyllin has been investigated using mutagenic compounds with different mechanisms of action, including the monofunctional alkylating agents, N-methyl-N'-nitrosourea (MNU) and ethylmethanesulphonate (EMS); nitrosamines related to tobacco products, i.e. dimethyl-nitrosamine (DMN), N-nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosoamino)-1-(3-pyridinyl)-2-butanone (NNK); the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) and two of its metabolites, i.e. (-)-7 beta,8 alpha-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-diol) and (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE); and a complex mutagenic mixture, an extract and subfractions of Swedish moist oral snuff (SMOS). Mutagenicity was monitored with the Ames Salmonella/microsome assays (STY) and hprt V79 point mutation assay (V79). The effects of chlorophyllin on the mutagenicity of the nitrosamines in the STY assays were found to be complex. In the presence of either NNN or NNK, low concentrations of chlorophyllin actually potentiated the mutagenicity > 2-fold. However, at higher, but still non-toxic concentrations, chlorophyllin decreased the mutagenicity of both compounds. The same type of dose-response relationship for chlorophyllin was indicated in the V79 assay system with DMN, although the effect was much weaker. The results with STY were further confirmed by replacing chlorophyllin with another porphyrin compound, hemin. In contrast, biliverdin, a porphyrin structure without the central metal ion, was unable to potentiate the mutagenicity of NNK in STY.(ABSTRACT TRUNCATED AT 250 WORDS)

Margareta Curvall

Papers

Screening of tobacco smoke constituents for mutagenicity using the Ames' test.

Simultaneous determination of nicotine and cotinine in plasma using capillary column gas chromatography with nitrogen-sensitive detection

In vitro studies of biological effects of cigarette smoke condensate. II. Induction of sister-chromatid exchanges in human lymphocytes by weakly acidic, semivolatile constituents.

Swedish snus and the GothiaTek® standard

Chlorophyllin is both a positive and negative modifier of mutagenicity.