Structural Biochemistry/Cytochrome P450 Enzyme

Introduction

The P450 catalytic cycle

Cytochrome P450 proteins are found in the genomes of virtually all organisms. Their amino-acid sequences are extremely diverse, but their structural fold has remained the same throughout evolution. Their origins could be traced back in vitro studies on the metabolism of steroids, drugs, and carcinogens. P450s are the enzymes that play a major role in drug metabolism and accounts for about 75% of the contribution of enzymes to the metabolism of marketed drugs.The mechanism of the cytochrome P450 enzyme can be compared to a blowtorch. As the P450 enzymes catalyzes regiospecific and stereospecific oxidative attack on non-activated hydrocarbons at physiological temperatures. But such a reaction also being uncatalyzed would require very high temperature and would be nonspecific. Not all the mechanisms for P450 are well understood. An example of an understood mechanism would be cytochrome P450’s activity in the liver being that it can encode a liver enzyme in which enables for it to metabolizes a series of known drugs. The CYP2D6 genome, which is a type of P450 enzyme, will determine how a person responds to a certain type of drug such as antipsychotics and antidepressants.What the enzyme does is it metabolizes potentially toxic compounds in the body allowing one to know if the drug is effective.

Use of P450

Marine animals can accumulate environmental contaminants in their blubber over time at concentrations known to be harmful to laboratory animals. The Cytochrome P450 enzyme is widely used as a biomarker for signs of exposure of molecular effects that could have taken placed. High concentrations of organochlorine pollutants are common in oceans and can affect the endocrine, reproductive, immune and nervous systems of animals and show evidences of skin and liver damage along with thymic atrophy, weight loss and neurobehavioral problems.A type of Cytochrome P450 known as CYP1A1 was induced into the skin biopsy section of the animal and it showed staining in three different cell types: the endothelial cells composing the lining of all blood vessels including capillaries, the smooth muscle cells present in larger blood vessels, and fibroblasts. These stains shows evidence that the environment is polluted and shows how pollutants can affect the animals that were exposed. From this it helps scientists find ways to reduce and find out what is contaminating the ocean.

Limitations

The physiological limitations to Cytochrome P450 enzymes are that ingesting certain types of foods can inhibit it. Eating a grapefruit can inhibit the P450 and can prevent detoxification from occurring. This affects the drug metabolism as if P450 is blocked, then a drug can potentially harm a person and poison them. In some cases the drug will not be as effective as it would be regularly.Another example of a physiological limitation is that the Cytochrome P450 instead of reducing toxicity it could potentially convert some drugs into toxic products. An example of this would be acetaminophen, which is found in painkillers such as Tylenol, too much acetaminophen will cause a negative affect and will cause toxic harm to one’s health.

The limitations to the practical application of this defense system to predict the effects of pollutants in the case of the ocean, is that most of the marine animals are protected by the government and scientist cannot induce them with the P450 enzyme, they instead use laboratory animals to conduct the experiment. This leads to just theories on if P450 being a successful biomarker. Also the lack of knowledge of P450 enzymes can pose a limitation, as we do not completely understand how all the P450 enzymes work. The practical application of this defense system to predict the effects of pollutants from a human stand point is that there are so many different types of P450 enzymes that we do not know all of them and their effects. So we cannot use P450 to exactly distinguish what carcinogens and cancerous chemicals affect. Also some of the P450 enzymes are embedded in membranes of the Endoplasmic Reticulum, which makes it hard to identify the structure, which makes it hard to study the different types of enzymes and this is a big limitation.

Application in Medicine

Medicine only works as expected in fewer than half of the people who take them. Environmental and lifestyle factors can explain this but individual variability in response to medicines is the main cause. This can be attributed to variants in the genes that make cytochrome P450 proteins. These proteins process many of the drugs we take. Because each person’s set of genes is a little different, the proteins that the genes encode are also slightly different. These changes can affect how the cytochrome P450 works on drugs.

References

2. http://toxsci.oxfordjournals.org/content/80/2/268.full.pdf

3. http://rusynlab.unc.edu/publications/course_data/Guengerich_2008.pdf

4. http://www.aapsj.org/articles/aapsj0801/aapsj080112/aapsj080112.pdf

5. http://genomebiology.com/content/pdf/gb-2000-1-6-reviews3003.pdf

6. U.S. Department of Health and Human Services. The New Genetics. October 2006.<http://www.nigms.nih.gov>.