The Molecular Perspective: Polycyclic Aromatic Hydrocarbons
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Correspondence: David S. Goodsell, Ph.D., Associate Professor, 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@scripps.edu Website: http://www.scripps.edu/pub/goodsell
Smoking is an unlikely method for delivery of small molecules. After all, it burns up most of your material. However, smoking is prevalent because it delivers a fine, volatile smoke of the remaining material, which rapidly enters the body at the point where the bloodstream is most exposed. By definition, the flame cannot be clean; it must allow the nicotine, cannabinoids, or opiates to survive in the smoke. Unfortunately, this flame also performs a multitude of uncontrolled chemical reactions, yielding thousands of exotic, and occasionally carcinogenic, compounds.
Among this collection of incomplete combustion products is a family of polycyclic aromatic hydrocarbons. These are large, flat molecules built of a collection of fused benzene-like rings. These compounds show up whenever organic material is burned: when smoking, at barbeques, and in the slower geological combustion that formed oil and coal.
Polycyclic aromatic hydrocarbons, since they are rich in carbon and are hydrophobic, pass easily through cell membranes and travel quickly into cells. Once inside, cells use their detoxification machinery to try to remove it. The first step is to attach some hand-holds onto these slippery molecules. The cytochrome p450 enzymes add oxygen atoms to the rings, making them more water soluble and creating anchors for attachment of larger groups, like sugars or glutathione. Normally, these modified molecules are excreted safely from the body. Unfortunately, some of the intermediate forms are highly dangerous and cause genetic damage before they can be removed.
One of the best-studied examples is benzopyrene, shown in Figure 1 (the "a" in the name is chemical shorthand that refers to the geometry of connection in the five fused rings). It does not attack DNA itself, but a nasty intermediate is formed within cells, with a reactive epoxide ring. This modified molecule is perfectly designed to be a mutagen. The flat, planar ring looks just like a DNA base, so the molecule slips into the stack of bases comfortably. Then, the reactive epoxide attacks a neighboring adenine or guanine nucleotide, forming a covalent bond.
Figure 1. Polycyclic aromatic hydrocarbons are large planar molecules. As shown at the bottom, they are modified in cells by addition of phenol or epoxide groups. The modified form of benzopyrene shown here is a potent mutagen.
The DNA adducts, with a bulky aromatic ring attached to the base, block replication and transcription, stopping the action of helicases and topoisomerases. However, this is a fairly common problem since the world is filled with these molecules, so our cells have methods to repair the damage, as shown in Figure 2. Unfortunately, these enzymes occasionally make mistakes, creating a mutation. And since the polycyclic aromatic hydrocarbons pick their sites at random, these mutations can appear in essential portions of the genome, in some cases leading to cancer.
Figure 2. This remarkable structure shows a DNA polymerase that specializes in lesion bypasses, shown in blue. The red strand of DNA has a benzopyrene adduct, shown in purple. The enzyme is caught in the process of pairing the next nucleotide, shown in yellow, to the DNA strand. Notice how benzopyrene is sandwiched between the yellow nucleotide and the upper base of the new DNA strand, shown in orange. Atomic coordinates were taken from entry 1s0m at the Protein Data Bank (www.pdb.org).
FURTHER READING
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999:91;1194–1210.
Pfeifer GP, Denissenko MF, Olivier M et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002:21;7435–7451.
Ling H, Sayer JM, Plosky BS et al. Crystal structure of a benzo pyrene diol epoxide adduct in a ternary complex with a DNA polymerase. Proc Natl Acad Sci USA 2004:101;2265–2269.(David S. Goodsell)
Smoking is an unlikely method for delivery of small molecules. After all, it burns up most of your material. However, smoking is prevalent because it delivers a fine, volatile smoke of the remaining material, which rapidly enters the body at the point where the bloodstream is most exposed. By definition, the flame cannot be clean; it must allow the nicotine, cannabinoids, or opiates to survive in the smoke. Unfortunately, this flame also performs a multitude of uncontrolled chemical reactions, yielding thousands of exotic, and occasionally carcinogenic, compounds.
Among this collection of incomplete combustion products is a family of polycyclic aromatic hydrocarbons. These are large, flat molecules built of a collection of fused benzene-like rings. These compounds show up whenever organic material is burned: when smoking, at barbeques, and in the slower geological combustion that formed oil and coal.
Polycyclic aromatic hydrocarbons, since they are rich in carbon and are hydrophobic, pass easily through cell membranes and travel quickly into cells. Once inside, cells use their detoxification machinery to try to remove it. The first step is to attach some hand-holds onto these slippery molecules. The cytochrome p450 enzymes add oxygen atoms to the rings, making them more water soluble and creating anchors for attachment of larger groups, like sugars or glutathione. Normally, these modified molecules are excreted safely from the body. Unfortunately, some of the intermediate forms are highly dangerous and cause genetic damage before they can be removed.
One of the best-studied examples is benzopyrene, shown in Figure 1 (the "a" in the name is chemical shorthand that refers to the geometry of connection in the five fused rings). It does not attack DNA itself, but a nasty intermediate is formed within cells, with a reactive epoxide ring. This modified molecule is perfectly designed to be a mutagen. The flat, planar ring looks just like a DNA base, so the molecule slips into the stack of bases comfortably. Then, the reactive epoxide attacks a neighboring adenine or guanine nucleotide, forming a covalent bond.
Figure 1. Polycyclic aromatic hydrocarbons are large planar molecules. As shown at the bottom, they are modified in cells by addition of phenol or epoxide groups. The modified form of benzopyrene shown here is a potent mutagen.
The DNA adducts, with a bulky aromatic ring attached to the base, block replication and transcription, stopping the action of helicases and topoisomerases. However, this is a fairly common problem since the world is filled with these molecules, so our cells have methods to repair the damage, as shown in Figure 2. Unfortunately, these enzymes occasionally make mistakes, creating a mutation. And since the polycyclic aromatic hydrocarbons pick their sites at random, these mutations can appear in essential portions of the genome, in some cases leading to cancer.
Figure 2. This remarkable structure shows a DNA polymerase that specializes in lesion bypasses, shown in blue. The red strand of DNA has a benzopyrene adduct, shown in purple. The enzyme is caught in the process of pairing the next nucleotide, shown in yellow, to the DNA strand. Notice how benzopyrene is sandwiched between the yellow nucleotide and the upper base of the new DNA strand, shown in orange. Atomic coordinates were taken from entry 1s0m at the Protein Data Bank (www.pdb.org).
FURTHER READING
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999:91;1194–1210.
Pfeifer GP, Denissenko MF, Olivier M et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002:21;7435–7451.
Ling H, Sayer JM, Plosky BS et al. Crystal structure of a benzo pyrene diol epoxide adduct in a ternary complex with a DNA polymerase. Proc Natl Acad Sci USA 2004:101;2265–2269.(David S. Goodsell)