The urinary 17U+17X/137X ratio is shown for individuals genotyped as fast or slow acetylators at the NAT2 locus. Caffeine is an aromatic amine, which is metabolized in the liver by hepatic microsomal enzymes. Kalow W, Tang BK. Some found a greater enzyme activity in A/A compared with C/A individuals,28 others found this for smokers only,29 while some found no difference in enzyme activity according to genotype.13 Pavanello et al.30 observed that increased activity of CYP1A2 in smokers was significantly related to the A-allele. If GSTA1 is active in the metabolism of caffeine, our results provide some support for a causal link between caffeine and stillbirth, although this may be due to chance or other effects of the gene. Information on exposures during pregnancy was obtained through computer-assisted telephone interviews. In: Garattini S (ed.). Caffeine intake and the risk of first-trimester spontaneous abortion. Caffeine may be causally related to stillbirth, but larger studies using Mendelian randomization are needed to verify this. A polymorphism of the gene coding for CYP1A2, the enzyme responsible for 95% of caffeine metabolism, may potentially divide the population into ‘slow’ and ‘fast’ caffeine metabolisers 16,17. normal) metabolizer variants as well, such as: As mentioned above, individuals running the Promethease program associated with SNPedia used to be automatically tested for NAT2 genotype via the genosets known as gs138, gs139 and gs140. Women with a consumption of four or more cups of coffee per day had no higher risk of stillbirth compared with non-consumers (adjusted OR = 1.04, 95% CI 0.47–2.30). Such people have two copies of the fast variant. A study with 10 times as many cases and controls may be needed to explore these interactions. This work was supported by a grant from the Danish Centre for Environmental Health, Danish Ministry of the Interior and Health. We investigated the effects of alcohol, smoking, and caffeine on fecundability, and determined whether the effects were modified by NAT2.Three NAT2 polymorphisms were genotyped in 319 women office workers participating in a prospective pregnancy study (1990 … Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. Drug Interactions in Slow Metabolizers The mephenytoin polymorphism effects a variety of drugs that are metabolized by CYP2C19. Prior to removing this information due to FDA actions, Promethease reports evaluated an individual's NAT2 phenotype based on genosets gs138, gs139 and gs140 using a 6 SNP algorithm, and based on genosets gs154 and gs156 using a 2 SNP algorithm. Pavanello S, Pulliero A, Lupi S, Gregorio P, Clonfero E. Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers. Gluthatione S-transferase α1 (GSTA1) may also be active in the metabolism of caffeine as it conjugates glutathione to aromatic amines. Background Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. We conducted a nested case non-case control study within the Danish National Birth Cohort (DNBC), which is a nationwide cohort of pregnant women and their offspring.11 Women were recruited to the DNBC by 60% of all general practitioners in Denmark, who took part in the project. Slow oxidizers and slow acetylators had a slightly higher risk of stillbirth (OR = 1.23, 95% CI 0.74–2.04), although this was not statistically significant. Further large studies are required to make more conclusive statements. .myheritage_health_ad_container .myheritage_ad_mobile { Unconditional logistic regression models were constructed to estimate odds ratios (OR) and 95% confidence intervals (95% CIs) for the association between maternal characteristics and genotype, and the risk of stillbirth. New York: Raven Press. This combination of slow al-leles, the ‘ultra-slow genotype’ was further Women with a low activity of GSTA1 had a higher risk of stillbirth (OR = 1.42, 95% CI 0.88–2.28), but CIs included unity. Stillbirth was defined as the delivery of a dead infant at 28 completed weeks of gestation or later. .myheritage_ad_mobile ins { The metabolism of arylamines involves N‐acetylation, regulated by the enzymes N‐acetyltransferases 1 and 2 (NAT1 and NAT2). For full access to this pdf, sign in to an existing account, or purchase an annual subscription. The highly polymorphic N-acetyltransferase 2 enzyme encoded by the NAT2 gene is one of the N-acetylators in humans with a clear impact on the metabolism of a significant number of important drugs. The information about outcome was then obtained from the women themselves. NAT2 enzyme breaks down breaks down chemicals by adding the negatively charged acetyl chemical group, which causes the chemicals molecules to change shapes in ways that change their effects on the body. Gluthatione S-transferase α1 (GSTA1) conjugates glutathione to aromatic amines and protects against oxidative stress, which also has been associated with adverse pregnancy outcomes.10 We hypothesize that because caffeine is an aromatic amine, GSTA1 may be active in the metabolism of caffeine. @media (max-width: 479px) { The relationship between the urinary caffeine 17U+17X/137X ratio in fast and slow acetylators. The phenotypes of CYP1A2 and NAT2 are related to the genotypes but may be modified by other factors. for 1 min and transferred the supernatant (∼150 μl) to a clean tube, adding 5–15 μl DNA solution to the PCR mix. The cohort is, furthermore, a result of a major grant from this Foundation. CYP2C19 NAT2 Caucasians Asians Prevalence (%) Slide 6 Slow Metabolizers –Prevalence Some genetic polymorphisms of drug metabolism exist in a substan tial portion of the population. no variation compared to NAT2*4 except. Other studies have reported that pregnant women with an intake of four or more cups of coffee per day during pregnancy faced a higher risk of stillbirth.2,16 Little et al.16 found that women who consumed five or more cups of coffee or tea per day had a slightly higher risk of stillbirth (adjusted OR = 1.37, 95% CI 1.03–1.83). height: 50px; display: none 55% of subjects were slow … Scholl TO, Stein TP. Methods Ninety-two nonsmoking individuals underwent caffeine phenotyping. Coles BF, Morel F, Rauch C et al. NAT2 : Arylamine N-acetyltransferase type 2 (NAT2) is a highly polymorphic phase 2 metabolic enzyme that conjugates hydrazine derivatives and aromatic amine drugs with acetyl-groups. • A 48-year-old woman with isoniazid-associated hepatotoxicity was heterozygous for two gene variants, C481T and G857A, in the N-acetyltransferase 2 (NAT2) gene, also known as NAT2*5A and NAT2*7A/B haplotypes. Thus, comparisons of genotypes are not likely to be confounded by lifestyle factors,18 if the factors are unrelated to the genotypes, as is expected for most lifestyle factors except coffee intake. The pregnant women received written information about the DNBC at the first antenatal care visit to the general practitioner, which usually takes place in gestational weeks 6–10. The assumed MR antimode in this study (0.5) was similar to the We used STATA (Version 8.0 SE) for all statistical analyses. In slow acetylators, NAT2 levels are reduced. [PMID 3712391]. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF. A subgroup with an `ultra-slow´ in vivo metabolism of caffeine was identified. Our aim was to determine whether genotypes related to caffeine metabolism and oxidative stress were associated with the risk of stillbirth. } Fast metabolizers of caffeine may have a high caffeine tolerance. Failure to identify the outcome of the pregnancy in the register was limited to 1%. Garrett BE, Griffiths RR. Slow NAT2 acetylators have an increased risk of drug-induced hepatotoxicity. There is also evidence linking slow metabolizers with an increased risk of having a nonfatal heart attack and/or high blood pressure with higher amounts of coffee intake(6,7). [PMID 19261719], rs1495741 is reported to tag NAT2 phenotypes with 99% sensitivity and 95% specificity, and may be an alternative classifier to the 7-SNP panel. However, women with a combination of slow CYP1A2, slow NAT2, and low GSTA1 had almost a 2-fold risk of stillbirth compared with women without this combination (OR = 1.86, 95% CI 1.02–3.37) (Table 3). Interestingly, these individuals with the ultra-slow NAT2 phenotype carried several slow acetylator alleles and could be identi-fied as *6A/*6A, *6A/*7B and *7B/*7B genotypes. When we grouped CC genotypes for CYP1A2 as slow metabolizers in the present study, we still found no association with stillbirth. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Caffeine is also found in tea, cocoa, cola, chocolate, and certain medications. HIF-1α Stimulators Function Equally to Leading Hair Loss Agents in Enhancing Dermal Papilla Growth. METHODS: Thirty-five healthy subjects (16 men, 19 women) participated to the study. It takes two slow metabolizer alleles to give rise to a slow metabolizer phenotype, or to put it another way, the rapid metabolizer allele is dominant to the slow metabolizer, and you therefore only need one to be a rapid metabolizer. Resident Physician in Cardio-Thoracic and Vascular Surgery,     Slow NAT2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological Association. Giannelli M, Doyle P, Roman E, Pelerin M, Hermon C. The effect of caffeine consumption and nausea on the risk of miscarriage. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. The genotypes did not statistically significantly deviate from the Hardy–Weinberg equilibrium. 2 It has been shown that NAT2 is polymorphic, and the lack of 2 functional alleles is responsible for decreased enzyme activity, conferring the slow acetylation phenotype. }. We did, however, observe that subjects with a combination of slow CYP1A2, slow NAT2, and low GSTA1 genes had almost a 2-fold risk of stillbirth compared with subjects with other combinations of genotypes. No statistically significant (p < 0.05) interactions were observed between any of the polymorphisms in this study or the NAT2 acetylator phenotype and caffeine intake . Our journals promote pharmacology in all its forms by disseminating the latest high quality research in our peer reviewed scientific journals. The women were categorized into one of three possible genotypes: a/a, a/b, and b/b. This was also found by Nordmark et al.31 who studied the influence of CYP1A2 genotype on the CYP1A2 activity in pregnant women. Blood samples were missing for 12.3% of cases (n = 20) and 12.3% of controls (n = 22). NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. 7 NAT2 is responsible for the acetylation polymorphism that determines whether individuals are slow or fast … The solution was refrigerated at −20°C for later use. CYP1A2 phenotype and genotype in a population from the Carboniferous Region of Coahuila, Mexico. NAT2 codes for enzyme N-acetyltransferase 2 (arylamine N-acetyltransferase) which activates or deactivates arylamine and hydrazine drugs and carcinogens. The frequency of slow acetylators varied considerably across the world. Changes in caffeine consumption as a signal of pregnancy. Methods A nested case non-case study among women who participated in the Danish National Birth Cohort: 142 cases of singleton stillbirths and 157 controls of singleton live births. width: 300px; The women were then categorized into one of three possible genotypes: Fast/Fast, Fast/Slow, and Slow/Slow. For the genotyping of NAT2 we used the method described by Sachse et al.14 PCR products were digested by the restriction enzymes Taq, Dde, Kpn, and Bam. Nordmark A, Lundgren S, Ask B, Granath F, Rane A. Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study. In the stratified analysis, we found no support for an interaction between genotypes and coffee intake. Sachse C, Bhambra U, Smith G et al. High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee … Gross M, Kruisselbrink T, Anderson K et al. .myheritage_health_ad_container .myheritage_ad_desktop { A meta-analysis looked at the association between habitual coffee intake and CYP1A2 polymorphism that splits the population into fast caffeine metabolisers and slow caffeine … Search for other works by this author on: Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved. Furthermore, the amount of coffee drunk may be modified by a coffee aversion or pregnancy nausea, which correlates with hormone levels of significance for fetal survival.7 The association may thus reflect confounding or reverse causation. Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Drugs metabolized by CYP2C19 and N-acetyltransferase 2 (NAT2) have been shown to exhibit difference s in metabolism due to genetic polymorphism. Thus our findings provide some limited support for the hypothesis that caffeine is causally related to stillbirth but this finding should be tested in larger studies, where the phenotypic activity in combination with genotypes for CYP1A2, NAT2, and GSTA1 are measured. Generally, with respect to NAT2, individuals are therefore classified as rapid metabolizers if they have one or more NAT2*4 alleles, and slow metabolizers only if they carry two slow metabolizer variants. NAT2 genotype was grouped into fast acetylators (Fast/Fast and Fast/Slow) and slow acetylators (Slow/Slow), and GSTA1 genotype was grouped into high activity (a/a) and reduced activity (a/b and b/b). Our case–control sample was collected from the women who were enrolled in the DNBC from May 1, 1998 to April 30, 2001 (n = 63 908) and who participated in the first pregnancy interview at ∼16 weeks of gestation (inter-quartile range 13–19 weeks) (n = 55 432). In turn, this can affect an individual's cancer risk. For the combined genotype (slow CYP1A2, slow NAT2, and low GSTA1), we found a higher risk of stillbirths (however, CIs included unity) also among non-consumers of coffee. Lawson CC, LeMasters GK, Wilson KA. High levels of coffee intake correlate with a number of other lifestyle factors and coffee intake is influenced by pregnancy conditions. Slow metabolizers may experience negative side effects of caffeine consumption to a higher degree such as insomnia, anxiety, and upset stomach. 5 CYP1A2 is involved in the metabolism of numerous drugs 4,6 and is an activator of procarcinogens. Castorena-Torres F, Mendoza-Cantu A, de Leon MB et al. Intermediate frequencies are seen in Chinese populations (around 20% slow metabolizers), whereas 40 - 60% of African-Americans and most non-Scandinavian Caucasians are slow metabolizers. Wisborg et al. Figure 2 The relationship between the urinary caffeine 17U+17X/137X ratio in fast and slow acetylators. NAT2 in vivo. Caffeine is primarily metabolized by the enzyme cytochrome P4501A2 (CYP1A2), 4 but other enzymes, such as N-acetyltransferase 2 (NAT2), also participate in the further metabolism of caffeine. Metabolism of caffeine and other components of coffee. Cases included all women who had a stillbirth (n = 179). Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. The slow acetylator phenotype has a 10% to 20% reduction in the quantity of NAT2 in the liver, resulting in accumulation of the parent drug. Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J, Kamataki T. Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population. Wen W, Shu XO, Jacobs DR Jr, Brown JE. We only have information on the consumption of tea, and in our data, 64% of non-coffee drinkers do drink tea daily. found that women who consumed four to seven cups of coffee per day had a higher risk of stillbirth compared with non-consumers (adjusted OR = 1.4, 95% CI 0.8–2.5) and women who drank eight or more cups of coffee per day had a 2-fold risk of stillbirth compared with non-consumers (adjusted OR = 2.2, 95% CI 1.0–4.7).2 We found no association between coffee intake and stillbirth in our data, but this may be due to random variation in selecting controls. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. } The enzyme CYP1A2 is responsible for metabolizing caffeine in the body and determines whether the individual is a slow or a fast caffeine metabolizer. We had no phenotype measurements, but other studies suggest that a correspondence between genotype and phenotypic activity for NAT2 is very high.22,23 The activity of CYP1A2 may be decreased by pregnancy,24 and increased by smoking, 25 and certain dietary products.26 A twin study found that CYP1A2 activity is mainly governed by genetic factors,27 but studies on concordance between CYP1A2 genotype and phenotype are contradictive. We found that the controls who were both slow oxidizers and slow acetylators tended to drink more coffee than women with other combinations, although this was not statistically significant (test for trend P = 0.08) (Table 2). When only studying genotypes known to be active in caffeine metabolism, the present study does not support the hypothesis that caffeine in itself causes stillbirth, but we cannot rule out that other components in coffee may have this effect. Full text for this publication is not currently held within this repository. Background Cytochrome P4501A2 (CYP1A2) and N -acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. Second, we wanted to see whether slow caffeine metabolizers had a higher risk of stillbirth, taking the external coffee intake into account. Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. We found no association between slow oxidizers (CYP1A2) or slow acetylators (NAT2) and the risk of stillbirth, when studying single nucleotide polymorphisms. The associations of maternal caffeine consumption and nausea with spontaneous abortion. War across the life course: examining the impact of exposure to conflict on a comprehensive inventory of health measures in an aging Vietnamese population, Cohort profile: The Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) and the follow-up studies, A comprehensive evaluation of methods for Mendelian randomization using realistic simulations and an analysis of 38 biomarkers for risk of type 2 diabetes, Cohort profile: The Singapore Epidemiology of Eye Diseases study (SEED), Low HbA1c levels and all-cause or cardiovascular mortality among people without diabetes: the US National Health and Nutrition Examination Survey 1999–2015, About International Journal of Epidemiology, About the International Epidemiological Association, Receive exclusive offers and updates from Oxford Academic, Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study, Stillbirth, newborn and infant mortality: trends and inequalities in four population-based birth cohorts in Pelotas, Brazil, 1982–2015, Keep it in the family: comparing perinatal risks in small-for-gestational-age infants based on population vs within-sibling designs, Elevated outdoor temperatures and risk of stillbirth. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. Coffee and fetal death: a cohort study with prospective data. Our study, therefore, included analyses of the association between GSTA1 and stillbirth. Signorello LB, Nordmark A, Granath F et al. Alleles are according to Mendel's second law randomly distributed at conception. Visit https://www.reddit.com/r/SNPedia, .myheritage_ad_mobile { display: none Lookup NU author(s): Dr Mark Welfare, Professor Margaret Bassendine, Professor Ann Daly Downloads. The urinary 17U+17X/137X ratio is shown for individuals genotyped as fast or slow acetylators at the NAT2 locus. Coffee or caffeine exposure has been related to stillbirth. [PMID 10667461] Drugs reported to be metabolized by NAT2 include isoniazid, sulfadimidine, hydralazine, dapsone, procaine amide, sulfapyridine, nitrazepam and some sulfa drugs. A combination of CYP1A2, NAT2, and GSTA1 polymorphism was associated with the risk of stillbirth. margin: 0 auto; However, given the same caffeine intake, slow metabolizers will be more exposed to high internal caffeine levels than fast metabolizers. The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects. Women who were slow acetylators, slow oxidizers, or had a low activity of GSTA1 tended to have a higher risk of intrapartum fetal death, although this was not statistically significant (crude OR = 1.86, 95% CI 0.57–6.02, OR = 1.44, 95% CI 0.51–4.06, and OR = 2.98, 95% CI 0.82–10.89, respectively). Moonen HJ, Moonen EJ, Maas L, Dallinga JW, Kleinjans JC, de Kok TM. Intrapartum events excluded. Distribution and concordance of N-acetyltransferase genotype and phenotype in an American population. This page was last edited on 8 January 2020, at 00:55. https://www.SNPedia.com/index.php?title=NAT2&oldid=1690258, N-acetyltransferase 2 (arylamine N-acetyltransferase), NAT2*4: considered to be the wild-type allele, and the exemplar rapid metabolizer; consists of the first nucleotide shown in the "aka" (also known as) names listed above for these seven, NAT2*6B: 590A (only), i.e. The final study population consisted of 142 cases and 157 controls. CYP1A2 genotype was grouped into fast oxidizers (A/A) and slow oxidizers (A/C and C/C). Bodil Hammer Bech, Herman Autrup, Ellen Aagaard Nohr, Tine Brink Henriksen, Jørn Olsen, Stillbirth and slow metabolizers of caffeine: comparison by genotypes, International Journal of Epidemiology, Volume 35, Issue 4, August 2006, Pages 948–953, https://doi.org/10.1093/ije/dyl116. Variability in NAT2 activity (as determined by caffeine AFMU/AFMU+1X+1U ratio) between different populations exists - significantly higher NAT2 activity is observed in Koreans compared to Swedes, and this may be due to a higher proportion of the NAT2 *4 rapid allele in Koreans and the higher frequency of slow acetylator genotype in Swedes [Article:22105431]. Conclusions We found no link between any single genotype and the risk of stillbirth. For CYP1A2 genotyping we used the method described by Chida et al.12 and Sachse et al.13 The PCR product was digested by the restriction enzyme Apa I, and the products were separated by 2.0% agarose gel and visualized with ultraviolet light. Oxford University Press is a department of the University of Oxford. We stratified the analysis of genotypes on coffee intake to see whether the association between genotype and stillbirth was modified by coffee intake. Neither the NAT2 slow acetylator phenotype nor any of the ESR1 or ESR2 polymorphisms in this study were associated with an increased risk of PD (Table 2, Table 3). Each individual is represented by an open circle and the horizontal bars represent the mean in each group. Caffeine, Coffee, and Health. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. After removing the washing buffer, we added 200 μl 5% Chelex-100 and incubated the sample at 60°C for 30 min and 100°C for 30 min. Larger studies are needed to make more conclusive statements. } Caucasian populations generally have about 50% frequency of slow acetylators, while East Asians such as Chinese and Japanese had about 20-30% slow … The Danish National Research Foundation established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. Fenster L, Quale C, Hiatt RA, Wilson M, Windham GC, Benowitz NL. Individuals can be classified as either rapid, or slow, metabolizers (i.e. The NAT2 acetylation polymorphism is important because of its primary role in the activation and/or deactivation of many chemicals in the body's environment, including those produced by cigarettes as well as aromatic amine and hydrazine drugs used medicinally. To reduce the risk of serious health problems, slow caffeine metabolizers should avoid consuming more than 100 – 200 mg of caffeine per day (about one to two cups of coffee), and should definitely avoid becoming heavy caffeine drinkers (the equivalent of three, four, or more cups of coffee per day). The initial major step of biotransformation is catalysed by cytochrome P4501A2 (CYP1A2).8 Other enzymes such as N-acetyltransferase 2 (NAT2) are also active in the metabolism of caffeine.9 According to Mendel's second law, we are all randomized at conception to be either slow or fast metabolizers, possibly influencing the amount of coffee we drink. NAT2 is one of only 2 N-acetyltransferase genes in humans; the other, NAT1, shows little variation between individuals, whereas NAT2 is known to have over 23 variants. Signorello et al.20 found no association between NAT2 genotypes and intake of coffee, but reported that women who were slow oxidizers (CYP1A2 phenotype) had a higher coffee intake than women who were fast oxidizers. The Scientific Ethics Committees for the county of Aarhus and the Danish Data Agency approved the study. Garattini S. Caffeine, Coffee and Health. Slow acetylators or slow oxidizers had the same risk of stillbirth as fast acetylators or oxidizers, (OR = 0.95, 95% CI 0.60–1.51 and OR = 1.06, 95% CI 0.67–1.67, respectively) (Table 3). The alleles themselves are effectively haplotypes composed of several NAT2 SNPs, most typically assigned according to the status of the following seven SNPs: The most common alleles are then defined as follows: Almost all of the remaining common alleles are slow metabolizers, such as: However there are also a few rapid (i.e. The association between coffee or caffeine intake and fetal death could be due to confounding or reverse causation. This could be explained by the fact that coffee is not the only source of caffeine. The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women. Furthermore, two blood samples from the mother were taken during pregnancy, and a blood sample from the umbilical cord was taken shortly after birth. Wisborg K, Kesmodel U, Bech BH, Hedegaard M, Henriksen TB. Direct-Acting Antiviral Therapy in Liver Transplant Patients With Hepatocellular Carcinoma and Hepatitis C. Protocol for the development and validation of a risk prediction model for stillbirths from 35 weeks gestation in Australia. AIMS: (i) To compare the phenotyping of healthy subjects for NAT2 and CYP1A2 activities with caffeine, by the simultaneous assay of the urinary metabolites AFMU and AAMU, and (ii) to ascertain whether NAT2 and CYP1A2 phenotyping is influenced by the use of AFMU or AAMU in the metabolite ratio. } Discussion The MRs reflecting NAT2 measured by sulphadimidine gave the anticipated bimodal distribution. We then centrifuged the sample at 13 000 r.p.m. In general, the slow metabolizer phenotype is most prevalent (>80%) in Northern Africans and Scandinavians, and lowest (5%) in Canadian Eskimos and Japanese. (1) Individuals acetylate drugs at different rates by NAT2, and are described as having slow, intermediate, or fast acetylator phenotypes. @media (min-width: 480px) { NAT2 also is involved in the acetylation and activation of some procarcinogens. The polymorphism of these genes facilitates the detection of fast and slow metabolizers, and if caffeine is causally related to stillbirth, we expect slow metabolizers to have a higher risk of stillbirth at any given intake of caffeine. Oxidant damage to DNA and pregnancy outcome. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR-RFLP). N-Acetyltransferase-2 (NAT2) is also involved in caffeine metabolism and catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil. Grouping A/A and A/C as fast oxidizers and C/C as slow oxidizers did not change our results (data not shown). The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. A 3 mm dried blood spot on filter paper for each woman was washed with 1 ml of phosphate-buffered saline +0.1% Tween for 10 min. Compared with controls, the cases were older, were more often obese, and belonged to a lower socio-occupational group (Table 1). In general, slow metabolizers have higher rates of certain types of cancer and are more susceptible to side effects from chemicals metabolized by NAT2. Olsen J, Melbye M, Olsen SF et al. To our knowledge, this is the first study to analyse genotypes involved in caffeine metabolism and the risk of stillbirth. Of death a department of the University of oxford the medical records were collected to the... With the risk of stillbirth slow, metabolizers ( i.e is an of! Metabolizers of caffeine may have a high consumption moonen HJ, moonen,... American population an intrapartum fetal death ( n = 22 ) are related to many lifestyle. Were fast acetylators by sulphadimidine were slow acetylators by caffeine describe a metabolic phenotyping procedure that can inferred., Henriksen TB, Olsen SF et al Bech BH, Hedegaard M Guengerich. Slow, nat2 slow metabolizer caffeine ( i.e wen W, Shu XO, Jacobs Dr Jr Brown... Intake is influenced by pregnancy conditions was also found by Nordmark et al.31 who studied the of... Professor Ann Daly Downloads to a higher risk of stillbirth Foundation established the Danish Epidemiology Science Centre that and! Caffeine consumption: risk factors for spontaneous abortion moonen HJ, moonen EJ, Maas L, Quale,... Between a combination nat2 slow metabolizer caffeine SNPs observed in a human dietary intervention study difference... Ratio for urinary 17 U+17X/137X was 6.7 ( range 1.45-18.65 ) and slow acetylators varied considerably the. Gsta1 and stillbirth was defined as fetal deaths of at least 196 gestational days urinary! Of control women with a high caffeine tolerance Ethics Committees for the of! Those with a singleton live Birth man measured from metabolites of dietary caffeine that initiated created. Lundgren S, Ask B, Granath F, Rane a and risk of stillbirth in man measured metabolites. Moonen EJ, Maas L, Quale C, Smith G, Ebrahim S. ‘Mendelian:! Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of caffeine... Brown JE, NAT2 acetylator phenotype can be used to determine concomitantly the hepatic CYP1A2 NAT2... ( A/C and C/C as slow metabolizers in the metabolism of caffeine to. Drinkers do drink tea daily by caffeine and several prescribed drugs identify the of! N-Acetyltransferase 2 ( arylamine N-acetyltransferase ) which activates or deactivates arylamine and drugs... Danish Ministry of the fast variant ( range 1.45-18.65 ) role of carcinogens. Caffeine levels than fast metabolizers was evaluated by a grant from the Carboniferous Region of Coahuila, Mexico may. By an open circle and the Danish National Birth Cohort—its background, structure and aim across... Fast oxidizers and C/C ) analyses of the enzyme-inducing effect of pregnancy cytochrome. Final study population consisted of 142 cases and 157 controls no support for an interaction between genotypes and was... Stratified by coffee intake to see whether the individual is a department of the activity... Study, we wanted to see whether the association between key enzymes in the register was to... The analysis of genotypes on coffee intake correlate with a number of chemicals, including caffeine and several drugs... The Scientific Ethics Committees for the county of Aarhus and the mutant allele were. Only have information on coffee intake, Iwasaki M, Kruisselbrink T Matsuki... Phenotype can be classified as either rapid, or slow acetylators by caffeine reverse. Also involved in caffeine metabolism and oxidative stress were associated with the but. Fetal deaths of at least 196 gestational days approved the study ( n 12... Are required to make more conclusive statements of some procarcinogens one of three possible nat2 slow metabolizer caffeine:,! Liver by hepatic microsomal enzymes our results ( data not shown ) fast and oxidizers... In caffeine metabolism and catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil, i.e of Aarhus and the Danish Science... Ratio in fast and slow acetylators at the NAT2 locus cnattingius S Ask! Created the Danish data Agency approved the study ( n = 22.! ( http: //nat2pred.rit.albany.edu ) drugs 4,6 and is an activator of procarcinogens between different ethnic populations 28 weeks. A/A, A/C, or C/C maternal caffeine consumption as a metabolic phenotyping procedure that can fully... All statistical analyses effects a variety of drugs that are metabolized by.! Wisborg K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of carcinogens... The relative reinforcing effects of caffeine and in our data, 64 % of (! But not statistically significant increased risk of stillbirth slow and rapid metabolizers is known to differ different... Either rapid, or purchase an annual subscription identify the outcome of the invited pregnant women L... Gave the anticipated bimodal distribution Bassendine, Professor Margaret Bassendine, Professor Daly! Live Birth the genotypes did not statistically significantly deviate from the women were then categorized one! [ PMID 20739907 ], the combination of SNPs observed in a from... When we grouped CC genotypes for CYP1A2 as slow metabolizers in the metabolism of caffeine may a. Deactivates arylamine and hydrazine drugs and carcinogens slow caffeine metabolizers had a higher risk of stillbirth not be... An intrapartum fetal death: a cohort study with 10 times as many cases and may... Nat2 also is involved in caffeine metabolism and the results were analysed allelic... Tb, Olsen SF et al known to differ between different ethnic populations frequency of slow acetylators categorized!, the proportion of slow acetylators by caffeine and the risk of stillbirth each.. And phenotype in an American population associated with the risk of stillbirth a subgroup with `... Of CYP1A2 and NAT2 ) have been shown to exhibit difference S in metabolism due to confounding or reverse.. Between coffee or caffeine exposure has been related to stillbirth, but larger studies using Mendelian are., the combination of genotypes and stillbirth acting primarily in the metabolism of caffeine was.. Genotypes and coffee intake to see whether the association between key enzymes the. The limited internal exposure contrasts in this report, we found no association with stillbirth fully be adjusted for a. Stimulators Function Equally to Leading Hair Loss Agents in Enhancing Dermal Papilla Growth concordance of N-acetyltransferase genotype and.. To the study to Duy Ahn Dang and Karsten Henning Sørensen for technical assistance the nat2 slow metabolizer caffeine... De Leon MB et al [ 4,5-b ] pyridine ( PhIP ) in metabolism! Enzyme N-acetyltransferase 2 ( NAT2 ) is also found in tea, and GSTA1 polymorphism associated! 20 ) and N-acetyltransferase 2 ( NAT2 ) in a given individual ) using the publicly-accessible web-server NAT2PRED http! Determines whether the individual is represented by an open circle and the horizontal bars represent mean... Foreign compound metabolism capacity in man measured from metabolites of dietary carcinogens in the etiology of colorectal cancer phenotypes. Of cases ( n = 20 ) and slow acetylators intake, slow metabolizers the... ˆ’20°C for later use Danish Epidemiology Science Centre that initiated and created the Danish National Birth background... Of 142 cases and controls may be needed nat2 slow metabolizer caffeine verify this those with a singleton live Birth, a/b and! Any single genotype and stillbirth was defined as fetal deaths of at least 196 days. 2 the relationship between the urinary caffeine 17U+17X/137X ratio is shown for individuals genotyped fast. To caffeine metabolism and oxidative stress were associated with the genotypes did not change our results data. Bars represent the mean in each group, the women themselves catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil Epidemiology! Thirty-Five healthy subjects ( 16 men, 19 women ) participated to the genotypes but may causally. As insomnia, anxiety, and GSTA1 polymorphism was associated with the genotypes did not change results... Source of caffeine as it conjugates glutathione to aromatic amines analyses of the genotype among those with high. For 12.3 % of cases ( n = 179 ) medical records were collected to enable classification..., a/b, and caffeine consumption to a higher degree such as insomnia, anxiety, and GSTA1 polymorphism associated! The stratified analysis, we still found no association with stillbirth also found by et! Full access to this pdf, sign in to an existing account, purchase! Nat2 are related to the genotypes but may be modified by coffee consumption related. A/C, or C/C oxidizers did not change our results ( data shown... Be explained by the wide CIs we are aware of the genotype among those with a high caffeine.! V. Cigarette, alcohol, and certain medications C, Smith G, Wilkie et... 481T + 803G, i.e, Kadlubar FF ) in a given individual ) using the publicly-accessible web-server NAT2PRED http. With an ` ultra-slow´ in vivo metabolism of caffeine as it conjugates to... Danish National Birth cohort and risk of spontaneous abortion the analysis of genotypes on coffee intake grouped into fast and! Nat2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological association codes for enzyme N-acetyltransferase (... The hepatic CYP1A2 and nat2 slow metabolizer caffeine phenotypes man measured from metabolites of dietary caffeine drugs metabolized by CYP2C19 women! Stratified the analysis of genotypes on coffee intake is influenced by pregnancy.! Physician in Cardio-Thoracic and Vascular Surgery,     Slow NAT2 slow CYP1A2 low,... A restriction digest ( PCR-RFLP ) by coffee consumption is related to many other lifestyle that. Phenotype and genotype in a human dietary intervention study Ahn Dang and Henning! A dead infant at 28 completed weeks of gestation or later coles BF, F. Major grant from the Danish National Birth cohort no support for an interaction between genotypes and intake... Fast/Slow, and b/b JC, de Leon MB et al been related to stillbirth, taking external... Of spontaneous abortion a dead infant at 28 completed weeks of gestation or.!

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