Xenobiotic metabolism

Humans and other mammals are equipped with a sophisticated machinery to handle carcinogens and other xenobiotic compounds, present in the cigarette smoke (CS). The metabolism of xenobiotics includes oxidative reactions by phase I enzymes that convert lipophilic chemical compounds into their hydrophilic forms, followed by phase II conjugation enzymes, and finally the phase III membrane transporters 1. The second and the last play a role in the elimination of xenobiotic metabolites 1. The most prominent phase I enzymes are cytochrome P450s (also known as CYPs) that detoxify or activate xenobiotic compounds 1.

The roles of various CYPs on the metabolism of CS toxicants have been discussed elsewhere in great detail 2-6.

One central player in the xenobiotic metabolism is the transcription factor aryl hydrocarbon receptor (AHR) that is activated by xenobiotic compounds and regulates the expression of several target genes (e.g., CYP1A1, CYP1B1, among others).

Normally, the levels of CYPs in the lung are expressed at trace levels, but they are induced upon CS exposure 7. Studies have reported that bronchial tissues of smokers exhibit higher levels of CYPs (e.g., CYP1A1 and CYP1B1) as compared to nonsmokers 8-12. Smoking cessation can reverse the induction of CYP expression upon smoking 8.

Also in the liver, CS constituents can induce several liver xenobiotic metabolizing enzymes. These include cytochrome P450 enzymes and glutathione S-transferases, enzymes whose genetic polymorphisms have, in turn, been associated with a higher risk of CS-related diseases 13-16.


References

  1. Omiecinski, C. J. et al. Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicological sciences : an official journal of the Society of Toxicology 120 Suppl 1, S49-75 (2011)
  2. Hukkanen, J. et al. Metabolism and disposition kinetics of nicotine. Pharmacological reviews 57, 79-115 (2005)
  3. DeVore, N. M. et al. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes. The Journal of biological chemistry 287, 26576-26585 (2012)
  4. Shimada, T. Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug metabolism and pharmacokinetics , 257-276 (2006)
  5. Li, D. et al. Sensitivity to DNA damage induced by benzo(a)pyrene diol epoxide and risk of lung cancer: a case-control analysis. Cancer research 61, 1445-1450 (2001)
  6. Hecht, S. S. DNA adduct formation from tobacco-specific N-nitrosamines. Mutation research 424, 127-142 (1999)
  7. Ding, X. et al. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annual review of pharmacology and toxicology 43, 149-173 (2003)
  8. Beane, J. et al. Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression. Genome biology 8, R201 (2007)
  9. Spira, A. et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proceedings of the National Academy of Sciences of the United States of America 101, 10143-10148 (2004)
  10. Zhang, X. et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiological genomics 41, 1-8 (2010)
  11. Sridhar, S. et al. Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium. BMC genomics 9, 259 (2008)
  12. Thum, T. et al. Expression of xenobiotic metabolizing enzymes in different lung compartments of smokers and nonsmokers. Environmental health perspectives 114, 1655-1661 (2006)
  13. Zevin, S. et al. Drug interactions with tobacco smoking. An update. Clinical pharmacokinetics 36, 425-438 (1999)
  14. Smith, C. A. et al. Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 350, 630-633 (1997)
  15. Hayes, J. D. et al. Glutathione transferases. review of pharmacology and toxicology 45, 51-88 (2005)
  16. Daly, A. K. et al. Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility. Environmental health perspectives 102 Suppl 9, 55-61 (1994)

Xenobiotic metabolism Results

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