Human cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play crucial roles in drug detoxification, cellular metabolism, and homeostasis. They constitute a superfamily of enzymes responsible for the metabolism of various clinically relevant substances. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal function of CYPs.
The human genome encodes at least 57 CYPs, which are mainly expressed in the liver. Other organs involved include kidney, placenta, adrenal gland, gastrointestinal tract, and skin. CYPs are the most well-known drug-metabolizing enzymes, primarily operating within hepatocytes, and their principal function is to metabolize hosts of xenobiotics and clearance of potentially toxic compounds. They also help in the metabolism of taxanes and are usually metabolized in the liver.
CYP enzymes are considered the major enzyme family capable of catalyzing oxidative biotransformation (phase 1 metabolism) of most drugs. They are mainly found within the endoplasmic reticulum and mitochondria of liver cells but can also occur in other cells. CYP3A4 is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs.
CYPs are present in many tissues, such as the liver, intestine, lung, heart, and brain, and catalyze the phase I metabolism of conventional drugs. Dysregulation of CYP enzymes can lead to variability in drug pharmacokinetics and response.
| Article | Description | Site |
|---|---|---|
| Biochemistry, Cytochrome P450 – StatPearls | By B. Gilani · 2023 · Cited by 19 — Primarily situated within hepatocytes, their primary function is to metabolize a multitude of xenobiotics and facilitate the clearance of potentially toxic compounds. | www.ncbi.nlm.nih.gov |
| Cytochrome P450 | The hydroxylation of xenobiotics by CYP450 enzymes facilitates their conversion into hydrophilic derivatives, which are subsequently excreted with greater ease. | en.wikipedia.org |
| Cytochrome P450 – an overview | CYP450 plays a role in the metabolism of taxanes and is typically metabolized in the liver. A number of solid tumors, including those of the ovary, have been observed to express CYP450 enzyme activity. | www.sciencedirect.com |
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Where is the cytochrome P450 located in the body?
Role of CYP Enzymes in Humans. Within humans, CYP enzymes are mainly found within the endoplasmic reticulum and mitochondria of liver cells. However, they are also found in many other cells of the body. These membrane-bound proteins are involved in the metabolism of many harmful substrates, such as toxins.
Additionally, they 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.
Where are CYP450 enzymes found in the cell?
Role of CYP Enzymes in Humans. Within humans, CYP enzymes are mainly found within the endoplasmic reticulum and mitochondria of liver cells. However, they are also found in many other cells of the body. These membrane-bound proteins are involved in the metabolism of many harmful substrates, such as toxins.
Additionally, they 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.
What are P450 metabolizing enzymes?
Human cytochrome P450 (CYP) enzymes, which are membrane-bound hemoproteins, play a crucial role in drug detoxification, cellular metabolism, and homeostasis. In humans, almost 80 of oxidative metabolism and 50 of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. CYPs can also affect drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism in both metabolic organs and local sites of action.
The structures of CYPs have provided new insights into understanding drug metabolism mechanisms and exploiting CYPs as drug targets. Genetic polymorphisms, epigenetic changes in CYP genes, and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. This review summarizes and highlights the structural knowledge about CYPs and the major CYPs in drug metabolism, as well as genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response.
Drug metabolism can be divided into phase I and phase II reactions, with phase I reactions introducing reactive or polar groups into drugs, such as oxidation, reduction, and hydrolysis. Phase II reactions catalyze the conjugation of modified drugs to polar compounds, which may be further processed before being recognized by efflux transporters and pumped out of cells. However, the same metabolic process can also lead to the generation of reactive metabolites, which are toxic to the human body.
Where are drug metabolizing enzymes found?
Human liver CYP2C9 and CYP2C19 are homologous enzymes important to human drug metabolism. In fact, CYP2C9 is among the most highly expressed CYP enzymes in human liver, second only to CYP3A4. While the CYP2C enzymes are all found in liver, they are also in the intestine (Paine et al., 2006).
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Are CYP enzymes only in the liver?
Cytochrome P450 (CYP) is a terminal oxidase in the mixed function oxidase system, mainly located in the endoplasmic reticulum of the liver, but also in other organs including the brain, where it is present in all cell membranes (1–6).
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Where is the site of metabolism?
The liver The principal site of drug metabolism is the liver, although other organs (e. g. gut, lung, kidney) can to some extent metabolize drugs. Metabolism has two important effects. First, it normally inactivates the drug preventing further pharmacological activity (unless there are active metabolites).
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Where does CYP metabolism occur?
CYPs are predominantly expressed in the liver, but can also occur in the small intestine (where they may reduce drug bioavailability), lungs, placenta, and kidneys. Cytochrome enzymes catalyze oxidation and reduction.
Is CYP3A4 in the liver?
CYP3A4 is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs1.
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- Key Messages. CYP3A4 is responsible for the metabolism of more than 50% of medicines.
- CYP3A4 activity is absent in new-borns but reaches adult levels at around one year of age.
- The liver and small intestine have the highest CYP3A4 activity.
- Some important CYP3A4 interactions are due to intestinal rather than hepatic enzyme inhibition (eg, grapefruit).
- There is considerable variability in CYP3A4 activity in the population.
- Women have higher CYP3A4 activity than men.
- Potent inhibitors of CYP3A4 include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit.
- Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John’s Wort and glucocorticoids.
Cytochrome P450 enzymes are essential for the metabolism of many medicines and endogenous compounds. The CYP3A family is the most abundant subfamily of the CYP isoforms in the liver. There are at least four isoforms: 3A4, 3A5, 3A7 and 3A43 of which 3A4 is the most important 1.
Are CYP enzymes in the gut?
The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine.
How does CYP3A4 metabolize?
Cytochrome P450 3A4 (abbreviated CYP3A4 ) ( EC 1. 14. 13. 97 ) is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules ( xenobiotics ), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.
While many drugs are deactivated by CYP3A4, there are also some drugs that are activated by the enzyme. Some substances, such as some drugs and furanocoumarins present in grapefruit juice, interfere with the action of CYP3A4. These substances will, therefore, either amplify or weaken the action of those drugs that are modified by CYP3A4.
CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of this family, it is a hemoprotein, i. e. a protein containing a heme group with an iron atom. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22. 1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively-spliced transcript variants encoding different isoforms have been identified.
Is CYP3A4 in the gut?
Cytochrome P450 3A4 (CYP3A4) is present not only in the liver but also in the small intestine, where it functions as a barrier against xenobiotics. Some CYP3A4 substrates exhibit low bioavailability due to intestinal first pass metabolism.
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📹 Mechanism of Cytochrome P450 (CYP) metabolism, induction, and inhibition
A basic brief 33 second explanation of CYP450 metabolism and the mechanism and consequence of its induction and inhibition …
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