Search results for CYP3A4

Showing 15 results out of 23

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Protein (2 results from a total of 2)

Identifier: R-HSA-52639
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Primary external reference: UniProt: CYP3A4: P08684
Identifier: R-HSA-2980797
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Primary external reference: UniProt: CYP3A43: Q9HB55

Reaction (6 results from a total of 14)

Identifier: R-HSA-9678766
Species: Homo sapiens
Compartment: cytosol, endoplasmic reticulum membrane
These compounds are inhibitors of cytochrome P450 3A enzymes (von Moltke et al. 1999, Yeo & Yeo 2001, Xu et al. 2010, Temesgen 2013, Greenblatt & Harmatz 2015). Cytochrome P450 3A4 (CYP3A4) is the most broadly active drug-metabolizing enzyme in humans. It oxidizes and clears over half of all administered pharmaceuticals due to its promiscuity. By inhibiting CYP3A4, these drugs can enhance bioavailability and prolong the plasma half-life of antiretroviral drugs such as those used to treat HIV infection.
Identifier: R-HSA-211948
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, endoplasmic reticulum lumen
The CYP3A family are the most abundantly expressed P450s in human liver, accounting for around 50% of xenobiotic drug metabolism. CYP3A4 is the most abundant member of the family and possesses broad specificity to a range of xenobiotics. Loperamide (LOP), an antidiarrheal, is mainly metabolized to desmethylloperamide (DLOP) through the N-demethylation pathway. This initial N-demethylation is carried out by CYP3A4.
Identifier: R-HSA-9758674
Species: Homo sapiens
Compartment: cytosol, endoplasmic reticulum membrane
Prednisolone (PREDL) strongly induces the expression of cytochrome P450 3A4 (CYP3A4) in hepatic cells (Sumida et al, 2000; Usui et al, 2002). Co-application of the CYP3A4 inhibitor ketoconazole with predisolone decreased urinary output of the metabolite 6beta-hydroxyprednisolone (6βOH-PREDL) significantly (Zürcher et al, 1989). As CYP3A4 also hydroxylates cortisol to the 6betaOH-product (Peng et al, 2011) it is probable that CYP3A4 oxidizes PREDN to 6βOH-PREDN, and PREDL to 6βOH-PREDL.
Identifier: R-HSA-9756169
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, cytosol
Atorvastatin (ATV) is hydroxylated to hydroxy-metabolites, predominantly by cytochrome P450 3A4 (CYP3A4) (Fujino et al. 2004, Park et al. 2008). Here, ATV hydroxylation to 2-hydroxyatorvastatin (2-OH-ATV, aka ortho-hydroxyatorvastatin) is described.
Identifier: R-HSA-9756162
Species: Homo sapiens
Compartment: cytosol, endoplasmic reticulum membrane
Atorvastatin (ATV) is hydroxylated to hydroxy-metabolites, predominantly by cytochrome P450 3A4 (CYP3A4) (Fujino et al. 2004, Park et al. 2008). Here, ATV hydroxylation to 4-hydroxyatorvastatin (4-OH-ATV, aka para-hydroxyatorvastatin) is described.
Identifier: R-HSA-9756180
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, cytosol
Atorvastatin lactone (ATVL) is hydroxylated to hydroxy-metabolites, predominantly by cytochrome P450 3A4 (CYP3A4) (Park et al. 2008). Statin lactones are metabolized to a much higher extent than their acid forms by CYP enzymes, suggesting that metabolism of the lactone is the relevant pathway for atorvastatin elimination (Jacobsen et al. 2000, Fujino et al. 2004, Filppula et al. 2021). Described here is the formation of 4-hydroxyatorvastatin lactone (4-OH-ATVL).

Set (3 results from a total of 3)

Identifier: R-ALL-9679016
Compartment: cytosol
Identifier: R-HSA-9680941
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Identifier: R-HSA-5423680
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane

Complex (2 results from a total of 2)

Identifier: R-HSA-9679000
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Identifier: R-HSA-9680864
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane

Pathway (2 results from a total of 2)

Identifier: R-HSA-9754706
Species: Homo sapiens
Atorvastatin (ATV, brand name Lipitor), is a lipid-lowering drug of the statin class of medications. It inhibits the endogenous production of cholesterol in the liver, thereby lowering abnormally high cholesterol and lipid levels, and ultimately reducing the risk of cardiovascular disease. Statins inhibit the enzyme hydroxymethylglutaryl-coenzyme A reductase (HMGCR) , which catalyzes the critical step in cholesterol biosynthesis of HMG-CoA conversion to mevalonic acid. Statins are the most commonly prescribed medication for treating abnormal lipid levels (Malhotra & Goa 2001). ATV and its hydroxy-metabolites collectively inhibit HMGCR to reduce circulating low-density lipoprotein cholesterol.

ATV is transported in the blood almost exclusively bound to plasma proteins (>98%) (Lennernas 2003), and is subject to pre‑systemic clearance at the gastrointestinal tract and to first‑pass hepatic clearance, which explains its low systemic bioavailability (~12%) (Garcia et al. 2003). Organic anion transporters OATP1B1, OATP1B3 and OATP2B1, encoded by SLCO1B1, SLCO1B3, and SLCO2B1, respectively are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of drugs such as ATV (Kalliokoski & Niemi 2009).

In hepatocytes (and to a lesser extent, the GI tract), ATV can be hydroxylated by cytochrome P450 3A4 (CYP3A4) to hydroxy-metabolites, or undergo lactonization via an unstable acyl glucuronide intermediate to ATV lactone (ATVL) mediated by UGT1A3 and 1A1. ATVL may also be hydroxylated by CYP3A4 to hydroxylactone-metabolites. The lactone metabolites are inactive against HMGCR, but can be hydrolyzed via paraoxonases (PONs) to their corresponding hydroxy acids, which are active against HMGCR. Elimination of ATV and its metabolites is principally biliary with apparently no significant enterohepatic recirculation. Half-life (t1/2) is approximately 14 h for atorvastatin and 20–30 h for its metabolites (Schachter 2005).
Identifier: R-HSA-9679191
Species: Homo sapiens
The search for drugs to prevent or reduce the severity of human infection with SARS-CoV-1 or SARS-CoV-2 has centered on ones that are effective in treatment of human infections with other RNA viruses or in diminishing cytokine storms and other pathologies due to destructive host reactions. The interactions of a large number of these candidate drugs with their known viral and human protein targets are annotated, as are some drugs that inhibit Cytochrome P450 (CYP) oxidoreductases to prolong the plasma half-lives of antiviral drugs. In addition, effects of these drugs on unrelated essential human proteins, that might limit their use in vivo, are annotated.

A notable success of this search is a combination treatment, Paxlovid (NCT04960202), involving ritonavir, an inhibitor of CYP3A4 and CYP2B6 oxidoreductases, and nirmatrelvir, an inhibitor of SARS-CoV-2 3CLp protease, to block steps in maturation of viral replicase proteins (Hashemian et al. 2023).

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