Stem Cells, Vol. 19, No. 3, 263-264,
May 2001
© 2001 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Cytochrome P450
David S. Goodsell
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 www: http://www.scripps.edu/pub/goodsell
Each day we are barraged by a bestiary of exotic chemicals. Our food is filled with unpleasant compounds: the plants we eat fill themselves with complex poisons and cooking forms a variety of reactive scorched molecules. Living in an industrial society, we are subject to all manner of pollutants. Our vices dose us with depressants and stimulants. Personally, I continually challenge my body with high levels of theobromine. Fortunately, we effectively recognize, transform, and eliminate these dangerous molecules, rendering them harmless.
The human body is designed to absorb carbon-rich molecules, so that we can use the fats and vitamins in our diet. Unfortunately, many unwanted molecules, such as poisons and drugs, are also swept along with these nutrients into the body. To make matters worse, we are not designed for excreting these foreign carbon-rich molecules. The urinary system and digestive system are best at removing soluble compounds, such as urea. So, to ensure that carbon-rich toxins do not accumulate and poison us, we have a special system to take these molecules and make them more soluble, and thus more suitable for elimination.
Cytochrome P450 (Fig. 1
) is at the heart of this transformation system. It attaches a chemical "handle" onto these molecules. Then, in a second phase, other enzymes attach large soluble chemical groups to these handles, making the entire molecule more water soluble. Cytochrome P450 and the second-phase enzymes are found predominantly in the liver, where they form a first line of defense against toxins. They are also quite common in the nasal mucosa, where they defend us against bad odors.
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Figure 1. Cytochrome P450. The cytochrome P450 enzymes are remarkable not for their specificity, but for their lack of it. The active site is deep within the enzyme, next to a catalytic iron atom held at the center of a heme group. It can accommodate a variety of different carbon-rich molecules, pressing them tightly against the activated oxygen atom. P450 enzymes are found in nearly all organisms. The molecule shown here is from a bacterial cell that can grow using camphor as its sole source of carbon. This bacterial cytochrome P450 is free-floating in the cell, whereas our own enzymes are typically tethered to the surface of the endoplasmic reticulum. Coordinates were taken from entry 1dz8 at the Protein Data Bank (www.pdb.org).
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We make a collection of 15 or so different cytochrome P450 enzymes, each with slightly different jobs. All contain an iron atom held in a heme group. This iron atom takes electrons and uses them to charge an oxygen atom, making it highly reactive. This oxygen atom then can make many changes on different toxic molecules. It may add an alcoholic hydroxyl group or a three-membered epoxide ring. It may assist in the removal of hydrogen atoms or methyl groups, or assist in larger cleavages and rearrangements. Together, this small group of enzymes performs a Herculean range of reactions, using oxygen to attack thousands of different molecules. Some familiar molecules oxidized by cytochrome P450 include acetaminophen, caffeine, nicotine, diazepam, aniline and benzene. Cytochrome P450 enzymes also make occasional modifications to our own carbon-rich molecules, for instance, playing an essential role in the production of steroid hormones.
Cancer is one consequence of failure of this remarkable protective system. In some cases, the intermediate molecule produced by cytochrome P450 is far more dangerous than the original molecule. If it is not immediately inactivated in the second phase of the transformation, the oxygenated molecule can wreak havoc within the cell. Aflatoxin (Fig. 2) is one example. Aflatoxin is one of the major causes of liver cancer in the world, along with infection by hepatitis B. Cytochrome P450 adds a highly reactive epoxide group to aflatoxin, making it highly mutagenic. If not immediately disarmed with glutathione, it can attack DNA. The activated aflatoxin bonds directly to the DNA bases, forming a permanent linkage. Later, when the DNA is repaired or duplicated, the cellular machinery may misread the base sequence because of the intrusion of the foreign molecule, often causing a change in the base sequence or even causing a frame shift. If these mutations happen to fall within the regions encoding p53 or an oncogene, they may compromise the regulatory function of these molecules, ultimately leading to liver cancers. It is remarkable, however, how infrequently this actually occurs, given the diversity and quantities of poisonous molecules that we process daily.
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Figure 2. Aflatoxin biotransformation. Aflatoxin is produced by molds that contaminate peanuts and grains. Cytochrome P450 adds an oxygen atom (shown with an arrow), forming a reactive three-membered epoxide ring. Ideally, other enzymes then add a glutathione molecule to the epoxide, making it soluble and ready to be removed from the body. However, the epoxide intermediate is highly reactive, attacking DNA bases. In the lower figure, activated aflatoxin has bonded to a guanine ring in the DNA helix, and the flat carbon-rich ring system (shown in white and light gray) has inserted between the DNA bases. The extra bulk of the molecule distorts the helix (notice how stretched the helix is top to bottom) and leads to misreading of the genetic sequence when the DNA is replicated. Coordinates were taken from entry 1hm1 at the Protein Data Bank.
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ADDITIONAL READING
- Guengerich FP. Cytochrome P450 enzymes. Am Sci 1993;81:440-447.
- Mao H, Deng Z, Wang F et al. An intercalated and thermally stable FAPY adduct of aflatoxin B1 in a DNA duplex. Biochemistry 1998;37:4374-4387.
