For the first time, scientists have been able to "freeze in time" a mysterious process by which a critical enzyme metabolizes drugs and chemicals in food. By recreating this process in the lab, a team of researchers has solved a 40-year-old puzzle about changes in a family of enzymes produced by the liver that break down common drugs such as Tylenol, caffeine, and opiates, as well as nutrients in many foods.
The breakthrough discovery may help future researchers develop a wide range of more efficient and less-expensive drugs, household products, and other chemicals.
The scientists' findings were be published in the journal Science on 12 November 2010 [see below].
Michael Green, an associate professor of chemistry at Penn State University and lead author of the study, explained that scientists have speculated for decades that, during the process of metabolizing chemicals in the human liver, enzymes in the family named P450 pass through a critical chemical phase-change called "Compound I," whereby an oxygen molecule is temporarily added. However, until now, no one had actually seen the process happen or even had proven that it existed. "This phase change happens quickly, and P450 just as quickly changes back to its original state," Green explained. "So the challenge was trapping the enzyme at the exact moment that it went through the Compound I stage." First, Green and his colleagues grew one of the P450 enzymes in E.coli - bacteria found in the human gut. They then developed a method to cool the enzyme at just the right rate - one one-thousandth of a second - to "freeze in time" the formation process of Compound I.
Green also explained that, while all humans have a gene responsible for making the P450 enzymes, different populations of humans vary in which version of the gene they carry, and thus, which version of P450 they produce. Such P450 variations lead to differences in the way people respond to particular drugs. "With a drug such as caffeine, for example, one population of people might be fast metabolizers, while another might metabolize the drug more slowly," Green explained. "Because the risk of caffeine-induced heart attack may be higher in slow metabolizers, the ability to actually take a snapshot of the phase changes of the P450 enzymes could help us to understand better how certain chemicals can affect people in vastly different ways."
Green's P40 research may also aid future scientific discoveries in the field of pharmacology. "Adverse drug-drug interactions are a well-known problem," Green explained. "The answer to why some people have bad interactions could be understood at the level of the P450 enzymes and their state changes. Now that we can see those state changes on a molecular level, a deeper investigation is finally possible."
This research was supported by a grant from the National Science Foundation.
NSF Press Release
Key player in detoxification pathway isolated after decades of searching
Future studies of P450 compound I could lead to the more efficient design and creation of drugs.
Chemical reactions are happening all over the place all the time - on the sun, on the Earth and in our bodies. In many cases, enzymes help make these reactions occur. One family of enzymes, called cytochrome P450s (P450), is important because they help us eliminate toxins.
We know P450s are important to life of all kinds because they have been found in animals, plants, fungi and bacteria, but they are of special interest to humans because they are responsible for metabolism of about 75 percent of known pharmaceuticals.
"The reactions that P450s perform to detoxify a compound are interesting because they activate chemical bonds that are usually not reactive. Chemically speaking, this is a very difficult thing to do in a controlled way," said Michael Green of the department of chemistry at Penn State University. Green and a former student are authors of a paper describing a breakthrough in isolation of P450 compound I, an important chemical intermediate in the process of drug metabolism.
In terms of P450s, we humans aren't all the same. One person can be susceptible to poisoning by a toxin or drug more than another based on the levels of the different P450s they have in their liver, lungs and other organs. With such obvious medical and biological importance, these enzymes have been studied in great detail for many years, but exactly how they are able to catalyze these chemical reactions remains to be determined.
At the heart of the problem is P450 compound I. It is a highly reactive chemical species produced by the P450 enzyme to help metabolize a toxin or drug. Because of this extreme reactivity, compound I turns into something else before scientists have a chance to capture it. This has remained a problem for more than 40 years, prompting some to question its very existence.
"This work confirms the existence of compound I, and demonstrates that it can perform the type of chemical reactions for which P450s are known," stated Green. "Now that we can make this chemical species, we can begin to do larger scale studies to understand just how it performs this chemistry."
The research has impact on two major fronts: medicine and basic chemistry. A better understanding of both the biology and chemistry of this family of enzymes will drive research in both fields. Eventually, Green hopes these insights will help chemists understand how to better control the specificity of a given chemical reaction. This knowledge could make production of pharmaceuticals and a variety of commodity chemicals cheaper and more efficient.
Further Information:
Jonathan Rittle, Michael T. Green:
Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics.
In: Science; Vol. 330. no. 6006, pp. 933 - 937, 12 November 2010, DOI 10.1126/science.1193478
Stephen G. Sligar:
Glimpsing the Critical Intermediate in Cytochrome P450 Oxidations.
In: Science; Vol. 330. no. 6006, pp. 924 - 925, 12 November 2010, DOI 10.1126/science.1197881
Quelle: Penn State University, USA
Last update: 13.11.2010
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