(1) 4. kg caffeine improve 10-km cycling time, but only in those with the AA genotype. Additionally, there are clinically relevant CYP1A2 polymorphisms known to alter activity in adults, which may also have consequence for children who carry these variants. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene. Because clinical studies indicate a positive association between clozapine plasma concentration and antipsychotic response and since the extent of antipsychotic response varies markedly among patients, polymorphism of CYP1A2 and/or its regulators [e.g., aromatic hydrocarbon (AH) receptor] has been studied in an attempt to individualize clozapine therapy through identification of responders and nonresponders to the drug. In contrast, oral contraceptives, fluoroquinolones, and fluvoxamine inhibit CYP1A2 to a clinically relevant degree. The CYP1A2 gene regulates the synthesis of the enzyme, and small variations in this gene are associated with the efficiency of caffeine metabolism. Several other factors may also affect CYP1A2 enzyme expression and activity. Pavanello S, Pulliero A, Lupi S et al. Effect on CYP1A2 at lower doses of ritonavir is unknown. George Miller, in Blumgart's Surgery of the Liver, Pancreas and Biliary Tract (Fifth Edition), 2012. The information presented here is NOT A COMPLETE LIST of CYP1A2 inducers, inhibitors, and substrates Not all drug interactions are clinically significant. CYP1A2 participated in the abnormal lipid metabolism caused by alcohol stimulation through the PTEN/AKT/SREBP-1c pathway in liver cells. Furthermore, earlier studies including only single variants might have missed more complex haplotypes including several variants. It has monoxygenase activity for certain of these fatty acids in that it metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).[8]. This enzyme also biotransforms procarcinogens such as food-derived heterocyclic and aromatic mutagens, N-heterocyclics found in tobacco smoke, and difuranocoumarins to reactive carcinogens, as well as endogenous substances (e.g., estradiol, melatonin, and uroporphyrinogen). CYP1A2 is an enzyme found primarily in the liver that affects the metabolism of substrates such as estradiol (estrogen), propranolol (heart … The expression of UGTs 1A4, 2B4, and 2B7 was significantly downregulated in biopsies from patients with high inflammation scores, as was that of CYP1A2, whereas UGT expression was not affected by the degree of fibrosis (Congiu et al., 2002). Once these carcinogens are metabolized by CYP1A2, they also have to be eliminated by the body. We use cookies to help provide and enhance our service and tailor content and ads. 1 General background text Pharmacogenetics - CYP1A2 Last updated: 12 December 2013 Definitions in pharmacogenetics The genotype is the hereditary information about a specific characteristic of an individual. Increased risk of recurrent pregnancy loss induced by caffeine (Sata et al., 2005) and more recently decreased risk of nonfatal myocardial infarction (MI) induced by caffeine (Cornelis et al., 2006) have been associated with CYP1A2∗1F allele. CYP1A2 expression is not detectable until at least 1 month of age and reaches full maturity between 1 and 3 years of age (Ratanasavanh et al., 1991; Sonnier and Cresteil, 1998; Tanaka, 1998; Tateishi et al., 1997). [9][10][11][12] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. Aleksi Tornio, Janne T. Backman, in Advances in Pharmacology, 2018. 1b. CYP1A2 is an enzyme found primarily in the liver that affects the metabolism of substrates such as estradiol (estrogen), propranolol (heart medication), caffeine and Cymbalta (antidepressant). Summary of gene and mutations by cancer type from ICGC. CYP1A2 is the major hepatic isoform of the human CYP1A subfamily (Shimada et al., 1994). Their expression is regulated by the aryl hydrocarbon receptor (AhR) pathway. It accounts for about 10% to 15% of the total CYP content of human liver and is responsible for metabolism of 10% to 15% of drugs that undergo metabolism.28 Caffeine is a validated phenotyping agent used to assess the activity of CYP1A2.20 Clinically important drugs dependent on CYP1A2 for elimination include clozapine, cyclobenzaprine, imipramine, mexiletine, and theophylline. CYP1A2 and AhR loci have been identified in several genome-wide association studies to be linked with habitual coffee consumption (Amin et al., 2012; Coffee and Caffeine Genetics Consortium et al., 2015; Cornelis et al., 2011). grapefruitsap, fluvoxamine of het antibioticum ciprofloxacine ingenomen wordt kunnen serum waarden ervan dusdanig stijgen dat toxiciteit kan optreden. The CYP1A2 gene regulates the synthesis of the enzyme, and small variations in this gene are associated with the efficiency of caffeine metabolism. Both in vitro and in vivo findings agree that total demethylation of the CYP1A2 substrate caffeine increases exponentially with increasing postnatal age in the first 6 months of life (Carrier et al., 1988; Pons et al., 1988). Fraction of elimination attributable to CYP1A2*, Other CYPs involved Evidence of involvement of metabolite formed via in the metabolism CYP1A2 in the metabolism Summary of CYP1A2 (CP12, P3-450) expression in human tissue. These genetic factors account for approximately 35% to 75% of the variation in CYP1A2 activity.14 The frequency of these polymorphisms varies between different ethnic groups. CYP1A2 is not regarded as being a major contributor to forming the cited epoxides[12] but could act locally in certain tissues to do so. The activity of CYP1A2 as determined by caffeine clearance is reported to be decreased by approximately 30% at 14–18 weeks’ gestation, 50% at 24–28 weeks’ gestation, and 70% at 36–40 weeks’ gestation [27]. CYP1A2 accounts for ∼15% of the hepatic P450 content and is the main clearance mechanism for clinically important drugs such as theophylline, caffeine, clozapine, olanzapine, tizanidine, duloxetine, and ramelteon. CYP1A2 plays an important role in metabolism of drugs like clozapine, olanzapine, fluvoxamine, haloperidol, theophylline; biotransformation of endogenous compounds like melatonin, bilirubin, estrogens, procarcinogens, aflatoxin B1, and aromatic/heterocyclic amines as well as caffeine (Gunes and Dahl, 2008 ). Following is a table of selected substrates, inducers and inhibitors of CYP1A2. CYP1A2 is the active isoform responsible for the major N-dealkylation and S-oxidation metabolic pathways in humans. CYP1A2 - Explore an overview of CYP1A2, with a histogram displaying coding mutations, full tabulated details of all associated variants, tissue distribution and any drug resistance data. [7], CYP1A2 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. Moreover, combined genotypes of CYP1A2 rs762551 and CYP19A1 rs4646 or AhR Arg554Lys could further improve prediction of early AI-treatment response. Prawan and colleagues (2005) evaluated the relationship between CYP1A2, NAT1, and NAT2 polymorphisms and cholangiocarcinoma in Thailand. CYP1A2 belongs to the CYP1 family and its gene is located on chromosome 15 along with CYP1A1 and CYP1B1. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Sherwin, in Drug Metabolism in Diseases, 2017. This protein is involved in the breakdown of stimulants, drugs, nutrients, and other xenobiotics. It also is involved in turning aflatoxins (mold found on grain) into active compounds involved in liver cancer. The CYP1A2*1A/*1A genotype conferred a decreased risk of the cancer (adjusted OR, 0.28; 95% confidence interval [CI], 0.08 to 0.94), compared with CYP1A2*1F/1*F. Frequency distributions of rapid NAT2*13 and two slow alleles, *6B and *7A, were associated with lower cholangiocarcinoma risk. Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. This activity expels excess estrogen from the body. CYP1A2 is involved in the metabolism of fewer drugs than the enzymes previously discussed. Environmental and genetic factors are shown to influence the activity of CYP1A2. CYP1A2 localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. CYP3A and CYP2C protein levels were not significantly affected. Two CYP1A2 alleles (CYP1A2*1A wild type and *1F), six NAT1 alleles (NAT1*4 wild type, *3, *10, *11, *14A, and *14B), and seven NAT2 alleles (NAT2*4 wild type, *5, *6A, *6B, *7A, *7B, and *13), were analyzed. [5] In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene. Krekels, ... C.M.T. (10,11) Als deze substraten of medicijnen samen met een inhibitor zoals o.a. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780123860071000039, URL: https://www.sciencedirect.com/science/article/pii/B9780323612111000036, URL: https://www.sciencedirect.com/science/article/pii/B9780128018149000076, URL: https://www.sciencedirect.com/science/article/pii/S1054358918300267, URL: https://www.sciencedirect.com/science/article/pii/B9780128029497000080, URL: https://www.sciencedirect.com/science/article/pii/B9780128021019000181, URL: https://www.sciencedirect.com/science/article/pii/B9780323428736000226, URL: https://www.sciencedirect.com/science/article/pii/B978012802949700002X, URL: https://www.sciencedirect.com/science/article/pii/B9781437714548001089, Principles of Clinical Pharmacology (Third Edition), 2012, Impact of Pregnancy on Maternal Pharmacokinetics of Medications, William C. Schaffenburg, ... Cynthia M.C. What is the clinical indication for duloxetine? Exons 2–6 are highly conserved among the human, mouse, and rat. Using the metabolism of caffeine as a marker of activity in vivo, several investigators demonstrated high interindividual and interethnic variability in CYP1A2 activity. CYP1A2 expression and activity exhibit approximately 40-fold inter-individual variations in human liver (Gunes and Dahl, 2008). CYP1A2 is involved in the metabolism of, e.g., agomelatin, caffeine, clozapine, duloxetine, propranolol, tizanidine, and zolmitriptan, as well as some endogenous compounds, such as melatonin and estradiol. Meaning the more estrogen the less testosterone and progesterone. CYP1A2 encodes for an enzyme (cytochrome P450 family 1 subfamily A member 2) and catalyzes reactions involved in drug metabolism and synthesis of cholesterol, steroids, substances, and other lipids (). The CYP1A2∗1F variant appears to increase the clearance of caffeine in smokers; other SNPs, alleles, or haplotypes might increase or decrease caffeine metabolism. CYP1A2 International Cancer Genome Consortium. This protein is involved in the breakdown of stimulants, drugs, nutrients, and other xenobiotics. Caffeine metabolism is one of the best markers of CYP1A2 activity available in vitro and in vivo and has been used as an important tool to study the influence of genetic and nongenetic factors influencing CYP1A2 function. The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In vivo phenotyping of patients with mild and moderate liver disease revealed a 79% reduction in CYP2C19 activity (mephenytoin) compared with healthy controls, whereas CYP2D6 activities were not affected (Adedoyin et al., 1998). The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. [15] Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. CYP1A2*1C has been associated with decreased caffeine 3-demethylation in Japanese smokers, suggesting decreased inducibility by polycyclic aromatic hydrocarbons in cigarette smoke (Nakajima et al., 1999). The human CYP1A2 gene is located on chromosome 15 and contains seven exons. The enzyme CYP1A2 increasingly isinvolved in drug interactions as newmedications metabolized by thisenzyme are released. kg in those with the CC genotype. Meaning of CYTOCHROME P-450 CYP1A2. Numerous SNPs have been described in the CYP1A2 gene, and most of the nonsynonymous SNPs encode for allozymes (CYP1A2*2 to *21) with reduced enzyme activity than wild-types; however, these SNPs occur at a very low frequency (Gunes and Dahl, 2008; Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee). As a result, differences in inducibility by these variants, normal, diminished, or hyperinduction phenotypes may be observed. You have two copies of the CYP1A2 gene—one inherited from each of your parents—and each can be either a “fast” or “slow” version of the gene. CYP1A2 codes for a protein that belongs to the Cytochrome P450 family. DeKlotz, in, Comprehensive Dermatologic Drug Therapy (Fourth Edition), Yogita A. Ghodke-Puranik, Jatinder K. Lamba, in, Gunes and Dahl, 2008; Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee, Cornelis et al., 2011; Sulem et al., 2011; Amin et al., 2012; Cornelis et al., 2014, Newton-Cheh et al., 2009; Ehret et al., 2011; Palatini et al., 2009, Zhou, Ingelman-Sundberg, & Lauschke, 2017, Coffee and Caffeine Genetics Consortium et al., 2015, Sachse, Brockmoller, Bauer, & Roots, 1999, Hepatic Drug Metabolism in Pediatric Patients, Berthou et al., 1988; Sonnier and Cresteil, 1998, Ratanasavanh et al., 1991; Sonnier and Cresteil, 1998; Tanaka, 1998; Tateishi et al., 1997, Clinical and Translational Science (Second Edition), http://www.imm.ki.se/CYPalleles/cyp1a2.htm, Clozapine is a prototypical atypical antipsychotic whose metabolism covaries with, Practical Hepatic Pathology: a Diagnostic Approach (Second Edition), Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses, Molecular pathogenesis of biliary tract cancer, Blumgart's Surgery of the Liver, Pancreas and Biliary Tract (Fifth Edition). Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as cumin and turmeric, ingredients known to inhibit the enzyme.[16]. William C. Schaffenburg, ... Cynthia M.C. (1) 2. Ongeveer 5% van alle geneesmiddelen wordt gemetaboliseerd door het CYP1A2-enzym. Considerable inter-individual variability of up to 15-fold exists in the expression of CYP1A2.28 This has largely been attributed to induction by environmental agents such as tobacco smoke, cruciferous vegetables, and charcoal-grilled meat. 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. CYP1A2*1F allele has been associated with increased caffeine metabolism in Caucasian smokers (Ghotbi et al., 2007; Sachse et al., 1999). 1. The CYP1A2, NAT1, and NAT2 genes have been shown to be potential modifiers of an individual's susceptibility to certain types of cancers.