viernes, 27 de julio de 2018

What are Cytochrome P450 (CYP) Enzymes?

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By Hannah Simmons, BSc

The cytochrome P450 (CYP) enzymes are a protein superfamily involved in the synthesis and metabolism of drugs, toxins and normal cellular components.

Person holding out hand and holding several different types of pills.

Image Credit: yavyav / Shutterstock

The CYP family of enzymes have been identified in many organisms, including animals, plants, bacteria, and even in a few viruses. The name “cytochrome P450” is derived from several characteristics; they are bound to the membrane of cells (cyto) and contain heme pigment (chrome and P).

When bound to carbon monoxide, these proteins produce a spectrum with a wavelength at approximately 450 nm.

How do CYP enzymes work?

There are seven stages of the CYP catalytic cycle:

Firstly, the substrate binds to the CYP enzyme, inducing a conformational change and a spin state change of the heme iron.
The second stage is initial reduction reaction of the heme group (Fe3+). NAD(P)H transfers an electron to heme via the electron transfer chain, forming Fe2+.
Then, oxygen binds to the Fe2+ heme group, forming Fe2+O2, which eventually becomes Fe3+O2; a more stable molecule.
The fourth stage is the second reduction reaction, which forms Fe3+O22-.
The O22- then reacts with two protons, breaking the bond between the two oxygen molecules and forming (FeO)3+.
The heme-bound oxygen atom is then transferred to the substrate.
Finally, the product is released from the enzyme and the initial enzymatic state is returned.

CYP enzymes in humans

Within humans, CYP enzymes are mainly found within the endoplasmic reticulum and mitochondria of liver cells. These membrane-bound proteins are involved in the metabolism of many harmful substrates, such as drugs and toxins.

CYP enzymes are also important in the synthesis of many beneficial substrates, such as steroid hormones (such as estrogen and testosterone), fatty acids, and sterols (such as cholesterol and bile acids).

So far, 57 different CYP genes in 18 protein families have been identified in the human genome. Some of these enzymes have highly specific targets, such as aromatase, which only targets androgens to convert them into estrogens. However, some CYP genes have a wide range of function.

CYP enzymes in drug metabolism

One of the most studied roles of CYP enzymes is their involvment in drug metabolism. These proteins control the speed at which drugs are broken down, and the length of time that the drugs are present in the body.

An overactive CYP enzyme will render a drug ineffective, and the patient will experience no benefit from taking the medication. However, if these enzymes are not active enough, the drug can stay in the body for a prolonged duration leading to toxicity.

Of all the different CYP proteins that are present in the human body, six of them are involved in the metabolism of 90% of drugs. These proteins are CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A5.The most important are CYP3A4 and CYP2D6.

Genetic variations affecting CYP450 enzyme activity

Genetic variability within these enzymes greatly influences the rate at which drugs are broken down. Certain drugs can also inhibit or activate the enzyme or even cause harmful drug-to-drug interactions and adverse reactions.

For example, around 1 in 15 individuals can have an over reactive response to beta-blockers due to genetic variation.

Non-genetic factors affecting CYP450 enzyme activity

In addition to genetic variability, other factors can influence the function of these enzymes. Diet is one example. Grapefruit juice contains a molecule called flavanol that has inhibitory effects on the CYP enzyme and can slow down the metabolism of drugs, leading to stronger drug effects.

Other foods that activate the CYP enzymes include charcoal-grilled foods and cruciferous vegetables (e.g. broccoli).

An additional, non-dietary factor that affects the function of these enzymes is smoking. Smoking activates CYP1A2, increasing the speed at which drugs are metabolized.

CYP enzymes and personalized medicine

There is extensive research being carried out using CYP enzymes within the area of personalized medicine. Through the analysis of CYP450 gene variation, an effective drug dose can be prescribed, increasing the likelihood of successful treatment.

An example of a gene that has been investigated as a possible target for personalized medicine is the CYP2C9 gene, that is involved in the metabolism of warfarin.

The protein product of this gene controls the amount of warfarin that is required by each patient. Therefore, it has been suggested that by identifying the specific gene variant that a patient possesses, informed decisions could be made with respect to dosing. This can prevent the possibility of internal bleeding, a common and potentially dangerous side effect of warfarin.

Reviewed by Deepthi Sathyajith, MPharm