Endogenous formation of nitrosamines and oxidative DNA-damaging agents in tobacco users

Crit Rev Toxicol. 1996;26(2):149-61. doi: 10.3109/10408449609017928.


One-third of all cancers worldwide can be attributed to various tobacco habits. Both in tobacco smoke and smokeless tobacco, carcinogenic N-nitroso compounds (NOC) are implicated as DNA-damaging agents in cancers of the aerodigestive tract and the pancreas. The exposure from nitrosamines in certain types of tobacco use such as "toombak" in Sudan could be as high as a few milligrams per day. Using the N-nitrosoproline test, it has been shown that smoking contributes to endogenous nitrosation and likely increases NOC formation in vivo. Smokeless tobacco, most widely used in the form of chewing of betel quid (BQ) with tobacco, was shown to particularly enhance endogenous nitrosation in the oral cavity, a site where chewing habits are causally associated with cancer. Poor oral hygiene was found to contribute to the formation of nitrosamines in the oral cavity. The evidence so far accumulated demonstrates that tobacco habits increase endogenous NOC formation, thus adding to the burden of exposure by preformed carcinogenic NOC in tobacco products. In snuff dippers, the unexpected higher level of HPB released from hemoglobin, an exposure marker for carcinogenic tobacco-specific nitrosamines, has been attributed to the endogenous formation of these carcinogens. Recent studies have demonstrated that besides carcinogenic tobacco-specific nitrosamines, reactive oxygen species derived from BQ ingredients could also play a role in the etiology of oral cancer in chewers. Although the use of chemopreventive agents may block nitrosation reactions in vivo in tobacco users, cessation of tobacco habits is the only safe way for an efficient reduction of cancer risk, in view of the high exposure to other (preformed) tobacco-related carcinogens.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Areca
  • Carcinogens / chemistry
  • Carcinogens / metabolism*
  • DNA Damage*
  • Flavonoids*
  • Humans
  • Mouth / drug effects
  • Nitrosamines / adverse effects
  • Nitrosamines / chemistry
  • Nitrosamines / metabolism*
  • Nitrosamines / urine
  • Nitrosation
  • Nitroso Compounds / urine
  • Oral Hygiene
  • Phenols / metabolism
  • Plants, Medicinal
  • Plants, Toxic
  • Polymers / metabolism
  • Polyphenols
  • Reactive Oxygen Species / metabolism
  • Smoking / adverse effects*
  • Thiazoles / urine
  • Thiazolidines
  • Tobacco, Smokeless / adverse effects


  • Carcinogens
  • Flavonoids
  • Nitrosamines
  • Nitroso Compounds
  • Phenols
  • Polymers
  • Polyphenols
  • Reactive Oxygen Species
  • Thiazoles
  • Thiazolidines
  • N-nitrosothiazolidine-4-carboxylic acid
  • nitrosoproline