Index
They are proteins of a superfamily that contain heme as a cofactor and are therefore hemeproteins.
They use a variety of small and large molecules as substrates in enzymatic reactions .
They are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term “P450” is derived from the spectrophotometric peak at the wavelength of the enzyme’s maximum absorption (450 nm) when it is in the reduced state and complexed with carbon monoxide.
Function
The enzymes produced from the cytochrome P450 genes are involved in the formation (synthesis) and breakdown (metabolism) of various molecules and chemicals within cells.
Cytochrome P450 enzymes play a role in the synthesis of many molecules, including steroid hormones, certain fats (cholesterol and other fatty acids), and the acids used to digest fats (bile acids).
The additional enzymes in cytochrome P450 metabolize external substances, such as drugs that are ingested, and internal substances, such as toxins that form inside cells. There are approximately 60 cytochrome P450 genes in humans.
Cytochrome P450 enzymes are found primarily in liver cells, but they are also found in cells throughout the body.
Within cells, cytochrome P450 enzymes are found in a structure involved in the processing and transport of proteins (endoplasmic reticulum) and the centers of energy-producing cells (mitochondria).
The enzymes found in the mitochondria are generally involved in the synthesis and metabolism of internal substances, while the enzymes in the endoplasmic reticulum generally metabolize external substances, mainly drugs and environmental pollutants.
Common variations (polymorphisms) in cytochrome P450 genes can affect enzyme function. The effects of polymorphisms are mainly observed in the breakdown of drugs. Depending on the gene and polymorphism, drugs can be metabolized quickly or slowly.
If a cytochrome P450 enzyme metabolizes a drug slowly, the drug remains active longer and less is needed to get the desired effect.
A rapidly metabolized drug breaks down sooner and a higher dose is needed to be effective. Cytochrome P450 enzymes represent 70-80% of the enzymes involved in drug metabolism.
Each cytochrome P450 gene is named with CYP, indicating that it is part of the cytochrome P450 gene family.
The gene is also given a number associated with a specific group within the gene family, a letter representing the gene’s subfamily, and a number assigned to the specific gene within the subfamily. For example, the cytochrome P450 gene that is in group 27, subfamily A, gene 1 is written as CYP27A1.
Diseases caused by mutations in the cytochrome P450 genes generally involve the accumulation of substances in the body that are harmful in large amounts or that prevent the production of other necessary molecules.
Examples of genes in this gene family: CYP1B1, CYP2C9, CYP2C19, CYP4V2, CYP11B1, CYP11B2, CYP17A1, CYP19A1, CYP21A2, CYP27B1.
The removal of foreign compounds (xenobiotics) such as drugs and toxins from the body is an essential process designed to protect against possible toxicity from the food we eat.
The decomposed food in the stomach is absorbed by the small intestine and then transported directly to the liver through the portal vein. This allows the liver time to detoxify compounds before they are distributed through the circulatory system.
In the liver, there are two main types of metabolism that deal with xenobiotics, and a third that deals with their transport.
Phases
Phase I metabolism produces small chemical changes that make a compound more hydrophilic, so it can be effectively eliminated by the kidneys.
These reactions generally involve adding or unmasking a hydroxyl group , or some other hydrophilic group such as an amine or sulfhydryl group, and generally involve hydrolysis, oxidation, or reduction mechanisms. Cytochrome P450 enzymes are responsible for most phase I reactions.
Phase II metabolism occurs if phase I is insufficient to remove a compound from the circulation, or if phase I generates a reactive metabolite. These reactions generally involve adding a large polar group (conjugation reaction), such as glucuronide, to further increase the solubility of the compound.
Often the functional groups generated in phase I reactions are necessary for the union of polar groups in phase II (although in some cases phase II reactions can occur on their own).
Transferase enzymes are responsible for most phase II reactions, for example, uridine diphosphoglucuronosyl transferase (UDT), N-acetyl transferase (NAT), glutathione S-transferase (GST), and sulfotransferase (ST).
Phase III involves drug transporters, which influence the effect, absorption, distribution, and elimination of a drug.
Drug transporters move drugs across cell barriers, and as such can be directed to sites of accumulation. They are found in the epithelial and endothelial cells of the liver, gastrointestinal tract, kidney, blood-brain barrier, and other organs.
