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90-432: 1TQN , 1W0E , 1W0F , 1W0G , 2J0D , 2V0M , 3NXU , 3TJS , 3UA1 , 4I3Q , 4I4G , 4I4H , 4K9T , 4K9U , 4K9V , 4K9W , 4K9X , 4NY4 , 5A1P , 5A1R , 4D6Z , 4D75 , 4D78 , 4D7D 1576 n/a ENSG00000160868 n/a P08684 n/a NM_001202855 NM_001202856 NM_001202857 NM_017460 n/a NP_001189784 NP_059488 n/a Cytochrome P450 3A4 (abbreviated CYP3A4 ) ( EC 1.14.13.97 )

180-506: A "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice". Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. For the relief of such pain, paracetamol is inferior to ibuprofen. Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than

270-403: A 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid . This change in consequence contributes to an increased human defense against cholestasis . Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 ( EC 1.14.14.1 ), which acts on a similar range of substrates. CYP3A4 increases to approximately 40% of adult levels in

360-464: A degree of dose dependence. The association between paracetamol use and asthma in children has been a matter of controversy. However, the most recent research suggests that there is no association, and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen. In recommended doses, the side effects of paracetamol are mild to non-existent. In contrast to aspirin, it

450-409: A dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice. After being taken by mouth, paracetamol is rapidly absorbed from the small intestine , while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same. In the same subjects,

540-487: A fatal interaction with drugs like astemizole or terfenadine . The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine ", and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with

630-409: A possible increase in the risk of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy. Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma , but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. Paracetamol, in

720-493: A result, it has been described as over-prescribed for this application. In addition, low-quality clinical data indicates that when used for the common cold , paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat , malaise , sneezing , or cough . For people in critical care , paracetamol decreases body temperature by only 0.2–0.3   °C more than control interventions and has no effect on their mortality . It did not change

810-408: A small-scale meta-analysis was also associated with a 20–30 % increase in autism spectrum disorder , attention deficit hyperactivity disorder , and conduct disorder , with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and whether there was potential bias in the findings. There is also an argument that

900-416: A transcript variant of CYP3A4. Alternatively-spliced transcript variants encoding different isoforms have been identified. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes . The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of steroids (including cholesterol ), and other lipids . The CYP3A4 protein localizes to

990-618: A wide range of activities that include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid ). The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs . This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity. Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands , although four amino acids positively selected in humans led to

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1080-447: Is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a " radical clock ". In 1998, various researchers showed that 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 . In some cases, this can lead to

1170-414: Is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain . It is a widely used over-the-counter medication . Common brand names include Tylenol and Panadol . Paracetamol relieves pain in both acute mild migraine and episodic tension headache . At a standard dose, paracetamol slightly reduces fever; it is inferior to ibuprofen in that respect, and

1260-429: 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

1350-785: Is associated with 1.9 times higher risk of peptic ulcer. Those who take it regularly at a higher dose (more than 2–3   g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events. Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23 % and kidney cancer by 28 %. Paracetamol slightly but significantly increases blood pressure and heart rate. A 2022 double-blind, placebo-controlled, crossover study has provided evidence that daily, high-dose use (4 g per day) of paracetamol increases systolic BP. A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows

1440-454: Is converted to sulfate by sulfation enzymes SULT1A1 , SULT1A3 , and SULT1E1 . A minor metabolic pathway (5–15 %) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1 , forms a toxic metabolite known as NAPQI ( N -acetyl- p -benzoquinone imine). NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione . The non-toxic conjugate APAP-GSH

1530-629: Is different from the 'FORMAT NUMBER' Oxidation /reduction reactions; transfer of H and O atoms or electrons from one substance to another Similarity between enzymatic reactions can be calculated by using bond changes, reaction centres or substructure metrics (formerly EC-BLAST], now the EMBL-EBI Enzyme Portal). Before the development of the EC number system, enzymes were named in an arbitrary fashion, and names like old yellow enzyme and malic enzyme that give little or no clue as to what reaction

1620-464: Is dose-dependent: it increases from 63 % for 500   mg dose to 89 % for 1000   mg dose. Its plasma terminal elimination half-life is 1.9–2.5 hours, and volume of distribution is roughly 50   L. Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21 %. The concentration in serum after a typical dose of paracetamol usually peaks below 30   μg/mL (200   μmol/L). After 4 hours,

1710-507: Is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it. Kidney failure is also a possible side effect. Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (t max ) to paracetamol peak blood plasma concentration (C max ), and increase C max . Medications slowing gastric emptying such as propantheline and morphine lengthen t max and decrease C max . The interaction with morphine may result in patients failing to achieve

1800-433: Is lacking. Paracetamol is effective for acute migraine: 39 % of people experience pain relief at one hour compared with 20 % in the control group. The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine". Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently. However,

1890-406: Is likely to be a function of the rate of enterocyte renewal ; an indirect approach based on the recovery of activity following exposure to grapefruit juice yields 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. Co-crystallization is difficult since

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1980-523: Is not a blood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation. Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects. Prolonged daily use may cause kidney or liver damage. Paracetamol is metabolized by the liver and is hepatotoxic ; side effects may be more likely in chronic alcoholics or patients with liver damage. Until 2010 paracetamol

2070-403: Is not activated by rifampicin and human PXR is not activated by pregnenolone 16α-carbonitrile In order to facilitate study of CYP3A4 functional pathways in vivo, mouse strains have been developed using transgenes in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in

2160-683: Is not recommended; however, doses may be alternated if required. Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea . It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient. The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain. It appears to provide only small and not clinically important benefits in osteoarthritis . American College of Rheumatology and Arthritis Foundation guideline for

2250-446: Is nothing like that of ibuprofen. Increase in risk-taking behavior is possible. According to the U.S. Food and Drug Administration (FDA), the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis , Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions. In clinical trials for osteoarthritis ,

2340-627: Is on the World Health Organization's List of Essential Medicines . Paracetamol is available as a generic medication , with brand names including Tylenol and Panadol among others . In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5   million prescriptions. Paracetamol is used for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear. As

2430-461: Is reduced to 4-aminophenol by hydrogenation over Raney nickel . In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91 % yield of 4-aminophenol. An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in

2520-430: Is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. Chronic users of paracetamol may have a higher risk of developing blood cancer . Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects . However, indications exist of

2610-454: Is sometimes followed by dehydrogenation, leading to more complex metabolites. An example of a molecule that undergoes more than one reaction due to CYP3A4 includes tamoxifen , which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide. Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes. The first pathway suggested

2700-413: Is superior to either drug alone. The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant. The evidence in its favor for the use in low back pain, cancer pain , and neuropathic pain is insufficient. In the short term, paracetamol is safe and effective when used as directed. Short term adverse effects are uncommon and similar to ibuprofen, but paracetamol

2790-438: Is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity. Yet another minor but important direction of metabolism is deacetylation of 1–2 % of paracetamol to form p -aminophenol . p -Aminophenol

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2880-506: Is the foremost cause of acute liver failure in the Western world , and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly in 1852 by Charles Frédéric Gerhardt . It is the most commonly used medication for pain and fever in both the United States and Europe. It

2970-475: 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

3060-443: Is then converted in the brain by fatty acid amide hydrolase into AM404 , a compound that may be partially responsible for the analgesic action of paracetamol. The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol , which

3150-505: Is typically safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for long-term use. Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen. Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding , and abnormal liver function tests . The recommended maximum daily dose for an adult is three to four grams. Higher doses may lead to toxicity, including liver failure . Paracetamol poisoning

3240-443: Is unclear. Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed. It does not prevent febrile seizures . It appears that 0.2   °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies. Based on this, some physicians advocate using higher doses that may decrease

3330-709: The CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo . It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates. CYP3A4 alleles that have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism. By contrast, CYP3A4*1G allele has more potent enzymatic activity compared to CYP3A4*1A (the wild-type allele). Variability in CYP3A4 function can be determined noninvasively by

3420-517: The XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in

3510-539: The endoplasmic reticulum , and its expression is induced by glucocorticoids and some pharmacological agents. Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism; substrates include acetaminophen (paracetamol), codeine , ciclosporin (cyclosporin), diazepam , erythromycin , and chloroquine . The enzyme also metabolizes some steroids and carcinogens . Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from

3600-410: The erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (C- N -methyl)- erythromycin . CYP3A4 is induced by a wide variety of ligands . These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to

3690-689: The International Congress of Biochemistry in Brussels set up the Commission on Enzymes under the chairmanship of Malcolm Dixon in 1955. The first version was published in 1961, and the Enzyme Commission was dissolved at that time, though its name lives on in the term EC Number . The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992 as

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3780-445: The U.S. than overdose of any other pharmacological substance. According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25 % of the emergency department visits, 10 % of

3870-409: The active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly,

3960-458: The analgesic effect of paracetamol. In 2018, Suemaru et al . found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the TRPV1 receptors and a decrease in neuronal excitability by hyperpolarization of neurons. The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru et al ., acetaminophen and its active metabolite AM404 show

4050-433: The anti-inflammatory action of paracetamol is slight. The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. The second mechanism centers on the paracetamol metabolite AM404 . This metabolite has been detected in

4140-492: The aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29 % of those who took the combination were pain-free as compared with 21 % on paracetamol and 18 % on placebo. The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as

4230-432: The benefits of its use for fever are unclear, particularly in the context of fever of viral origins. The aspirin/paracetamol/caffeine combination also helps with both conditions where the pain is mild and is recommended as a first-line treatment for them. Paracetamol is effective for post- surgical pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and

4320-427: The body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins are toxicated into their toxic forms (see table below for examples) . CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids. EETs have a wide range of activities including

4410-466: The brains of animals and cerebrospinal fluid of humans taking paracetamol. It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase . AM404 is a weak agonist of cannabinoid receptors CB1 and CB2 , an inhibitor of endocannabinoid transporter , and a potent activator of TRPV1 receptor. This and other research indicate that the endocannabinoid system and TRPV1 may play an important role in

4500-420: The case of the histamine H 1 -receptor antagonist terfenadine . Recently CYP3A4 has also been identified in the brain, but its role in the central nervous system is still unknown. Cytochrome P450 enzymes perform an assortment of modifications on 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

4590-477: The class. The substrates of CYP3A4 are: Inhibitors of CYP3A4 are classified by potency : The inhibitors of CYP3A4 are the following substances. Strong and moderate CYP3A4 inducers are drugs that decrease the AUC of sensitive substrates of a given pathway where CYP3A4 is involved by ≥80 percent and ≥50 to <80 percent, respectively. Weak inducers decrease the AUC by ≥20 to <50 percent. The inducers of CYP3A4 are

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4680-500: The concentration is usually less than 10   μg/mL (66   μmol/L). Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation , and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5 % of the drug is excreted unchanged in the urine. Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70 % of the drug metabolism. Additional 25–35 % of paracetamol

4770-421: The drug. Treatment is aimed at removing the paracetamol from the body and replenishing glutathione . Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N -acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease

4860-425: The enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation. By studying animal models and keeping in mind

4950-412: 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

5040-478: The following substances. Click on genes, proteins and metabolites below to link to respective articles. This article incorporates text from the United States National Library of Medicine , which is in the public domain . Enzyme Commission number EC numbers do not specify enzymes but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze

5130-409: The fourth month of life and 72% at 12 months. Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. CP3A4 is the major CYP enzyme in the intestine. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed, as in

5220-476: The greatest effects when juice is taken an hour previous to administration of the drug. In addition to grapefruit, other fruits have similar effects. Noni ( Morinda citrifolia ), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4. Pomegranate juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans. While over 28 single nucleotide polymorphisms (SNPs) have been identified in

5310-800: The hospitalizations, and 25 % of the deaths." Overdoses are frequently related to high-dose recreational use of prescription opioids , as these opioids are most often combined with paracetamol. The overdose risk may be heightened by frequent consumption of alcohol. Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms . The first symptoms of overdose usually begin several hours after ingestion, with nausea , vomiting , sweating, and pain as acute liver failure starts. People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by

5400-432: The inhibition of cyclooxygenase (COX) and actions of its metabolite N-arachidonoylphenolamine (AM404). Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors . Paracetamol inhibits prostaglandin synthesis by reducing

5490-406: The innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways. Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of the enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours. Turnover of gut CYP3A4

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5580-399: The large number, consistency, and robust designs of the studies provide strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On

5670-643: The last version published as a printed book, contains 3196 different enzymes. Supplements 1-4 were published 1993–1999. Subsequent supplements have been published electronically, at the website of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. In August 2018, the IUBMB modified the system by adding the top-level EC 7 category containing translocases. Acetaminophen Paracetamol , or acetaminophen ,

5760-417: The letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme. Preliminary EC numbers exist and have an 'n' as part of the fourth (serial) digit (e.g. EC 3.5.1.n3). For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes: NB:The enzyme classification number

5850-412: The liver. This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway. In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity. CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances. Due to

5940-417: The management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective. The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required. Essentially

6030-764: The median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 mRNA transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women. CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR

6120-412: The metabolism of endogenous and exogenous compounds. These include hydroxylation , epoxidation of olefins, aromatic oxidation , heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity. Hydroxylation of an sp C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand. In fact, hydroxylation

6210-450: The number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain. After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding

6300-419: The other hand, several studies did not find any association. The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage, and for the shortest time. In pregnancy, paracetamol and metoclopramide are deemed safe as are NSAIDs until the third trimester . Overdose of paracetamol is caused by taking more than

6390-603: The other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%. Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride . The effect is explained by these drugs inhibiting glucuronidation of paracetamol. Paracetamol raises plasma concentrations of ethinylestradiol by 22 % by inhibiting its sulfation. Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week. Paracetamol appears to exert its effects through two mechanisms:

6480-561: The outcome in febrile patients with stroke. The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage. Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection. The efficacy of paracetamol in children with fever

6570-436: The paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53 % of the participants, while the placebo helped only 7 %. Paracetamol fails to relieve procedural pain in newborn babies . For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). The studies to support or refute

6660-525: The paracetamol/codeine combination which is frequently prescribed for dental pain. The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone. Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations. A meta-analysis of general post-surgical pain, which included dental and other surgery, showed

6750-457: The peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours. Paracetamol's bioavailability

6840-504: The possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. Toxicity of paracetamol

6930-496: The presence of aflatoxin B1, M1, and G1. Indeed, 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. Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that

7020-468: The presence of hydrogen fluoride to a ketone, then the conversion of the ketone with hydroxylamine to a ketoxime , and finally the acid-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product. 4 -Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4 -aminophenol reacts in ammonia solution with

7110-419: The promotion of certain types of cancers (see epoxyeicosatetraenoic acid ). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids, which stimulate these cells to grow. The CYP3A4 enzyme is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE). 20-HETE has

7200-408: The recommended maximum daily dose of paracetamol for healthy adults (three or four grams), and can cause potentially fatal liver damage . A single dose should not exceed 1000 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours. While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to

7290-419: The same reaction, then they receive the same EC number. Furthermore, through convergent evolution , completely different protein folds can catalyze an identical reaction (these are sometimes called non-homologous isofunctional enzymes ) and therefore would be assigned the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence. Every enzyme code consists of

7380-455: The same recommendation was issued by EULAR for hand osteoarthritis. Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only. Paracetamol is ineffective for acute low back pain. No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol

7470-859: The substrates tend to have a low K D (between 5–150 μM) and low solubility in aqueous solutions. A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver nanoparticles produced from nanosphere lithography and analyzed via localized surface plasmon resonance spectroscopy (LSPR). These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including solid-state NMR , redox potentiometry, and steady-state enzyme kinetics . Following are lists of selected substrates , inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within

7560-417: The temperature by as much as 0.7   °C. Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis ), including children younger than 2 years old, with equivalent safety. Exacerbation of asthma occurs with similar frequency for both medications. Giving paracetamol and ibuprofen together at the same time to children under 5

7650-551: The therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear. There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics ). By and large, these suspicions have not been confirmed. Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital , primidone , isoniazid , and possibly St John's wort . On

7740-411: The use of more than one paracetamol-containing product over an extended period. Paracetamol toxicity has become the foremost cause of acute liver failure in the United States by 2003, and as of 2005 , paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. As of 2004, paracetamol overdose resulted in more calls to poison control centers in

7830-745: The use of paracetamol for cancer pain and neuropathic pain are lacking. There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain. Paracetamol helps ductal closure in patent ductus arteriosus . It is as effective for this purpose as ibuprofen or indomethacin , but results in less frequent gastrointestinal bleeding than ibuprofen. Its use for extremely low birth weight and gestational age infants however requires further study. Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency

7920-469: Was believed safe in pregnancy however, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn. Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood. One recent research study showed evidence that paracetamol can ease psychological pain, but more studies are needed to draw a stronger conclusion. Unlike aspirin, it

8010-457: Was catalyzed were in common use. Most of these names have fallen into disuse, though a few, especially proteolyic enzymes with very low specificity, such as pepsin and papain , are still used, as rational classification on the basis of specificity has been very difficult. By the 1950s the chaos was becoming intolerable, and after Hoffman-Ostenhof and Dixon and Webb had proposed somewhat similar schemes for classifying enzyme-catalyzed reactions,

8100-492: Was observed in 20 % of participants, this rate being similar to the ibuprofen group. Due to the absence of controlled studies , most of the information about the long-term safety of paracetamol comes from observational studies . These indicate a consistent pattern of increased mortality as well as cardiovascular ( stroke , myocardial infarction ), gastrointestinal ( ulcers , bleeding ) and renal adverse effects with increased dose of paracetamol. Use of paracetamol

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