This Article Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goodsell, D. S. Search for Related Content PubMed PubMed Citation Articles by Goodsell, D. S.

Cancer Biology

The Molecular Perspective: Alcohol

The Scripps Research Institute, La Jolla, California, USA

Correspondence: David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Web-site: http://www.scripps.edu/pub/goodsell

Received August 7, 2006; accepted for publication August 7, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Further Reading

 
After completing this course, the reader will be able to:

1. Discuss alcohol metabolism and its role in carcinogenesis.
   

Alcohol is a substance fraught with contradictions. It is a dangerously toxic solvent, yet it has been produced and consumed since the dawn of civilization. A glass of wine or a cocktail will complement any meal and smooth out the tensions of the day, but a few more drinks will inhibit reaction times, making the consumer the major threat currently on the road. A drink or two each day will reduce the risk for heart disease, a fact vividly shown in the unexpectedly low incidence of heart disease in the French in spite of a steady diet of rich foods. More heavy drinking, however, leads to myriad and widespread health problems, including cancer.

Alcohol is detoxified in the human body in two enzymatic steps (Fig. 1). First, alcohol is oxidized to acetaldehyde by the enzyme alcohol dehydrogenase. However, acetaldehyde is even more toxic than alcohol, so it is quickly oxidized to acetate by a second enzyme, aldehyde dehydrogenase. Both of these enzymes use the cofactor nicotinamide adenine dinucleotide (NAD) to provide the oxidizing power needed for these transformations. The need for the special redox talents of NAD places an important limit on the amount of alcohol that may be detoxified. Liver cells contain a limited supply of NAD, so these enzymes can act only as fast as it is recycled. This typically limits the detoxification rate to about one drink per hour—any additional alcohol stays in the circulation until the enzymes can get around to it.

View larger version (59K): [in this window] [in a new window]   Figure 1. Alcohol dehydrogenase and aldehyde dehydrogenase. Alcohol dehydrogenase (top) is found in the cell cytoplasm, where it uses a nicotinamide adenine dinucleotide (NAD) (green) to oxidize alcohol to acetaldehyde. Aldehyde dehydrogenase (bottom) is found in the mitochondria. It also uses NAD in its oxidation reaction. The site of the E487K mutation that inactivates the enzyme in much of the Asian population is shown in red, tucked between the different subunits. Atomic structures are taken from entries 1hsz and 1cw3 at the Protein Data Bank (http://www.pdb.org).

The strongest linkage of alcohol consumption with cancer is, quite expectedly, with cancers of the mouth, pharynx, larynx, and esophagus. The mechanisms of carcinogenesis are still a matter of study and debate, but two probable mechanisms involve the enzymes of alcohol detoxification. The acetaldehyde formed in the first step may be a major culprit. Acetaldehyde is a reactive compound that forms covalent complexes with proteins and DNA, and thus may act as a mutagen. Alcohol abuse also induces the production of a specific cytochrome P450 enzyme—CYP2E1 (Fig. 2)—which is able to work with alcohol dehydrogenase to oxidize alcohol. This enzyme, however, also forms dangerous reactive oxygen species and can activate environmental procarcinogens into their carcinogenic forms.

View larger version (58K): [in this window] [in a new window]   Figure 2. Cytochrome P450 2E1, which is induced by heavy alcohol consumption, uses a heme to oxidize many different small molecules, including ethanol. The similar 2C5 enzyme, which helps to metabolize half of known drugs, is shown here. Coordinates are taken from entry 1tqn at the Protein Data Bank.

	FURTHER READING

Top Learning Objectives Further Reading

 

1 Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol 2006;7: 149–156.[CrossRef][Medline]

2 Fleming M, Mihic SJ, Harris RA. Ethanol. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Eleventh Edition. New York: McGraw-Hill, 2006:591–606.

3 Seitz HK, Stickel F, Homann N. Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics. Int J Cancer 2004;108:483–487.[CrossRef][Medline]

This article has been cited by other articles:

				G. A. Barclay, J. Barbour, S. Stewart, C. P. Day, and E. Gilvarry Adverse physical effects of alcohol misuse Adv. Psychiatr. Treat., March 1, 2008; 14(2): 139 - 151. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goodsell, D. S. Search for Related Content PubMed PubMed Citation Articles by Goodsell, D. S.