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Tobacco carcinogens, their biomarkers and tobacco-induced cancer

A Correction to this article was published on 01 January 2004

Key Points

  • Tobacco products cause a variety of cancers, including those of the lung, oral cavity, nasal cavity, larynx, oropharynx, hypopharynx, oesophagus, stomach, liver, pancreas, bladder, ureter, kidney and cervix, and myeloid leukaemia. The carcinogens contained in tobacco products are responsible for these cancers.

  • There are more than 60 carcinogens in cigarette smoke and at least 16 in unburned tobacco. Among these, tobacco-specific nitrosamines (such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN)), polycyclic aromatic hydrocarbons (such as benzo[a]pyrene) and aromatic amines (such as 4-aminobiphenyl) seem to have an important role as causes of cancer.

  • Carcinogen biomarkers — DNA adducts, protein adducts and urinary metabolites — provide objective measures of carcinogen uptake and metabolic activation and detoxification in people who use, or are otherwise exposed to, tobacco products.

  • DNA adducts are central to the carcinogenic process as induced by tobacco products.

  • Among carcinogen biomarkers, DNA adducts potentially provide the most direct link to cancer, but there are still significant measurement problems. Protein adducts are useful alternatives to DNA adducts, and in some cases have provided significant mechanistic insights. Urinary metabolites are probably the most practical biomarkers and provide important information about carcinogen dose and metabolism.

  • Carcinogen biomarkers are important in establishing carcinogen dose in people who are exposed to tobacco products and in understanding mechanisms of carcinogenesis, and might ultimately be useful in predicting cancer risk.

Abstract

The devastating link between tobacco products and human cancers results from a powerful alliance of two factors — nicotine and carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?

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Figure 1: Scheme linking nicotine addiction and lung cancer through tobacco-smoke carcinogens.
Figure 2: Metabolic activation of tobacco-smoke carcinogens to DNA adducts known to be present in human lung.
Figure 3: Structures of some carcinogen–haemoglobin adducts and their conversion to analytes used as biomarkers.
Figure 4: Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides in urine.

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Acknowledgements

Research in the Hecht laboratory is supported by grants from the US National Institutes of Health, the American Cancer Society and the Flight Attendant Medical Research Institute. I thank S. G. Carmella, who has contributed substantially to our biomarker research, and my other colleagues and collaborators who have been involved in our research. I appreciate the editorial assistance of R. Carlson.

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Cancer.gov

bladder cancer

cervical cancer

colorectal cancer

hypopharyngeal cancer

laryngeal cancer

liver cancer

lung cancer

nasopharyngeal cancer

oesophageal cancer

oral cavity cancer

oropharyngeal cancer

pancreatic cancer

renal pelvis cancer

renal-cell carcinoma

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AKT

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GSTM1

MYC

protein kinase C

RAS

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Glossary

SMOKELESS TOBACCO PRODUCTS

Tobacco products that do not produce smoke, such as chewing tobacco and oral snuff.

ENVIRONMENTAL TOBACCO SMOKE

The material in indoor air (usually) that results from tobacco smoking. It is produced mainly by the release of smoke from the burning tip of a cigarette between puffs and the smoke exhaled by the smoker. Environmental tobacco smoke is also known as secondhand smoke.

CARCINOGEN BIOMARKERS

Quantifiable substances such as carcinogen–DNA adducts, carcinogen–protein adducts and urinary metabolites of carcinogens, which are derived from specific carcinogens.

MAINSTREAM SMOKE

The smoke that is emitted at the mouth end of the cigarette during puffing.

SIDESTREAM SMOKE

The smoke that is emitted from the burning cone between puffs, which comprises most environmental tobacco smoke.

STRONG CARCINOGEN

A carcinogen that reproducibly produces tumours in laboratory animals after treatment with relatively low doses (typically micrograms or milligrams).

WEAK CARCINOGEN

A carcinogen that produces tumours in laboratory animals only after administration of relatively high doses.

CO-CARCINOGENS

These increase the carcinogenic activity of carcinogens when administered simultaneously. Examples in cigarette smoke include catechol and methylcatechols.

TUMOUR PROMOTERS

These enhance carcinogenic activity when administered after the carcinogen. The best known example is 12-O-tetradecanoyl-phorbol-13-acetate (TPA), although this is not present in tobacco products. Tumour promoters of tobacco products are mainly uncharacterized.

DNA ADDUCT

A covalent binding product of a carcinogen or related substance or its metabolite to DNA.

PARTICULATE PHASE

That portion of tobacco smoke that is retained on a glass-fibre filter.

PROTEIN ADDUCT

A covalent binding product of a carcinogen or related substance, or its metabolite, to a protein.

32P-POSTLABELLING

A sensitive technique for detecting carcinogen–DNA adducts. DNA is hydrolysed enzymatically to nucleoside-3′-monophosphates, which are then labelled at the 5′-position with [γ-32P]ATP of high specific activity. The resulting labelled nucleoside diphosphates are then separated and detected.

ETHYLATING AGENT

A compound that can add an ethyl group to another molecule, such as DNA or a protein.

BAY REGION

The angular region, resembling a bay, of a polycyclic aromatic hydrocarbon molecule, such as the 4–5 positions of phenanthrene or the 10–12 positions of benzo[a]pyrene.

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Hecht, S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3, 733–744 (2003). https://doi.org/10.1038/nrc1190

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