Cytochrome P450, family 3, subfamily A, polypeptide 4

CYP3A4 Gene

An important enzyme in the body, mainly found in the liver and in the intestine.

Its purpose is to oxidize small foreign organic molecules or drugs, so that they can be removed from the body.

While many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme.

Some substances, such as grapefruit juice and some drugs, interfere with the action of CYP3A4, and either amplify or weaken the action of those drugs.

A member of the cytochrome P450 super family of oxidizing enzymes, and it is the most common one.

A hemoprotein, that is a protein containing a heme group with an iron atom, encoded by the CYP3A4 gene.

CYP3A gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1.

Cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components.

The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents.

This enzyme is involved in the metabolism of approximately half the drugs that are used

Drugs affected include acetaminophen, codeine, cyclosporin , diazepam, and erythromycin.

The enzyme also metabolizes some steroids and carcinogens.

Most drugs undergo deactivation by CYP3A4, either directly or by excretion from the body.

Many substances are bioactivated by CYP3A4 to form their active compounds.

Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7.

CYP3A4 increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.

CYP3A4 is predominantly found in the liver.

CYP3A4 it is also present in other organs and tissues of the body.

CYP3A4 in the intestine plays an important role in the metabolism of certain drugs.

CYP3A4 often allows prodrugs to be activated and absorbed – e.g. histamine H1-receptor antagonist terfenadine.

Cytochrome P450 enzymes modifies a variety of ligands, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds.

P450 activities include hydroxylation, epoxidation, aromatic oxidation, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity.

Hydroxylation of an sp3 C-H bond is one of the ways in which CYP3A4 affects its ligand.

Hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites, and the 2mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes.

Grapefruit juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their bioavailability.

Grapefruit juice, and grapefruit can lead to a fatal interaction with drugs like astemizole or terfenadine.

The effects of grapefruit last from 3–7 days, with the greatest effects when taken simultaneously with another drug.

Pomegranate juice also inhibits CYP3A4.

While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene.

Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT), which can estimate in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (14C-N-methyl)-erythromycin.

Due to the enzyme’s large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.

Increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight.

CYP3A4 activity linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.

Extensive presence in the intestinal mucosa.

The enzyme has sensitivity to starvation symptoms and is upregulated in defense of adverse effects.

Estimates of the turnover rate of human CYP3A4 vary widely: in the range of 26-140 hours.

In vitro methods give estimates from 26 to 79 hours.

Turnover of gut CYP3A4 a function of the rate of enterocyte renewal, with measurements in the 12 to 33 hour range.

Due to membrane-bound CYP3A4’s natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces.

Inhibitors of CYP3A4 can be classified by their potency:

Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease inclearance.

Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.

Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.

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