nat2 slow metabolizer caffeine

The phenotypes of CYP1A2 and NAT2 are related to the genotypes but may be modified by other factors. We used STATA (Version 8.0 SE) for all statistical analyses. Larger studies are needed to make more conclusive statements. Figure 2 The relationship between the urinary caffeine 17U+17X/137X ratio in fast and slow acetylators. detoxifiers). .myheritage_ad_mobile img, Oxford University Press is a department of the University of Oxford. Physical dependence increases the relative reinforcing effects of caffeine versus placebo. Giannelli M, Doyle P, Roman E, Pelerin M, Hermon C. The effect of caffeine consumption and nausea on the risk of miscarriage. Furthermore, we would expect a greater effect of the genotype among those with a high consumption. Adjusting for coffee intake or other possible confounders (parity, smoking, alcohol intake, pre-pregnancy body mass index, and socio-occupational status) did not substantially change the results (data not shown). Furthermore, two blood samples from the mother were taken during pregnancy, and a blood sample from the umbilical cord was taken shortly after birth. Individuals can be classified as either rapid, or slow, metabolizers (i.e. Lookup NU author(s): Dr Mark Welfare, Professor Margaret Bassendine, Professor Ann Daly Downloads. 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. Caffeine intake and the risk of first-trimester spontaneous abortion. 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. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. 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. @media (max-width: 479px) { 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. Each individual is represented by an open circle and the horizontal bars represent the mean in each group. 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. 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. We only have information on the consumption of tea, and in our data, 64% of non-coffee drinkers do drink tea daily. height: 50px; N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. margin: 0 auto; Caffeine is an aromatic amine, which is metabolized in the liver by hepatic microsomal enzymes. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Nordmark A, Lundgren S, Ask B, Granath F, Rane A. The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. 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. Blood samples were missing for 12.3% of cases (n = 20) and 12.3% of controls (n = 22). Coles BF, Morel F, Rauch C et al. High levels of coffee intake correlate with a number of other lifestyle factors and coffee intake is influenced by pregnancy conditions. We found no association between slow oxidizers (CYP1A2) or slow acetylators (NAT2) and the risk of stillbirth, when studying single nucleotide polymorphisms. Gross M, Kruisselbrink T, Anderson K et al. Wisborg K, Kesmodel U, Bech BH, Hedegaard M, Henriksen TB. Castorena-Torres F, Mendoza-Cantu A, de Leon MB et al. 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. Sachse C, Bhambra U, Smith G et al. found no association between enzyme activity of CYP1A2, xanthin oxidase, and NAT2, and spontaneous abortion when the phenotypes for these three enzymes were studied.19 In contrast, Signorello et al.20 found that women with a low CYP1A2 activity (phenotype) had a statistically significant lower risk of spontaneous abortion, and women who were slow acetylators (genotypes) had a somewhat higher risk of spontaneous abortion, although not statistically significant. The women were then categorized into one of three possible genotypes: Fast/Fast, Fast/Slow, and Slow/Slow. 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. We randomly sampled a similar number of control women with a singleton live birth. Sachse C, Smith G, Wilkie MJ et al. Oxidant damage to DNA and pregnancy outcome. The associations of maternal caffeine consumption and nausea with spontaneous abortion. 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). Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. Caffeine is also found in tea, cocoa, cola, chocolate, and certain medications. 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. Cases and controls were frequency-matched on parity. We found that 62% of controls were slow acetylators (NAT2), 47% were slow oxidizers (CYP1A2), and 59% had low activity of GSTA1. display: none The PCR-plate was read in the ABI 7000 sequence detector, and the results were analysed by allelic discrimination of the sequence detection software. 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. 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). Signorello LB, Nordmark A, Granath F et al. New York: Raven Press. 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. Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. After DNA analyses, the women were categorized into one of three possible genotypes: A/A, A/C, or C/C. The Scientific Ethics Committees for the county of Aarhus and the Danish Data Agency approved the study. In the stratified analysis, we found no support for an interaction between genotypes and coffee intake. 17960 Ensembl ENSG00000156006 ENSMUSG00000025588 UniProt P11245 P50294 RefSeq (mRNA) NM_000015 NM_008673 RefSeq (protein) NP_000006 NP_032699 Location (UCSC) Chr 8: 18.39 – 18.4 Mb n/a PubMed search Wikidata View/Edit Human View/Edit Mouse N-acetyltransferase 2 (arylamine N-acetyltransferase), also known as NAT2, is an enzyme which in humans is encoded by the NAT2 … Women with missing information on coffee intake were excluded from the study (n = 12). Kalow W, Tang BK. The final study population consisted of 142 cases and 157 controls. Recent publications report an association between coffee or caffeine intake during pregnancy and the risk of spontaneous abortion and stillbirth,2–6 but very few of these associations are causal. We are aware of the limited internal exposure contrasts in this comparison. 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. Odds ratios for stillbirtha according to genotypes, Odds ratios for stillbirtha according to genotype, stratified by coffee consumption. 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. Information on exposures during pregnancy was obtained through computer-assisted telephone interviews. Drug Interactions in Slow Metabolizers The mephenytoin polymorphism effects a variety of drugs that are metabolized by CYP2C19. a combination of SNPs observed in a given individual) using the publicly-accessible web-server NAT2PRED (http://nat2pred.rit.albany.edu). } Future studies on genes involved in caffeine metabolism should measure phenotypes to make sure that the polymorphisms of the genes studied actually express phenotypic differences. CYP1A2 genotype was grouped into fast oxidizers (A/A) and slow oxidizers (A/C and C/C). for 1 min and transferred the supernatant (∼150 μl) to a clean tube, adding 5–15 μl DNA solution to the PCR mix. Women who possessed a combination of the slow CYP1A2, the slow NAT2, and the low GSTA1 did have a higher risk of stillbirth, and according to the hypothesis that GSTA1 may be active in the metabolism of caffeine, we would expect women who had both slow CYP1A2 and slow NAT2, and low GSTA1 had a higher risk of stillbirth if caffeine was a causal factor. The frequency of slow acetylators varied considerably across the world. NAT2 may also refer to SLC38A1 . 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. New York: Raven Press. Compared with controls, the cases were older, were more often obese, and belonged to a lower socio-occupational group (Table 1). 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). The genotype is, thus, a propensity score for caffeine exposure, and comparing genotypes stratified on coffee intake is expected to be unconfounded and not subject to reverse causation. The interaction was evaluated by a likelihood ratio test. [PMID 16416399]. 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. The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects. HIF-1α Stimulators Function Equally to Leading Hair Loss Agents in Enhancing Dermal Papilla Growth. Stillbirth was defined as the delivery of a dead infant at 28 completed weeks of gestation or later. However, there are limited studies on N-acetylation phenotypes and NAT2 genotypes among Emiratis, and thus this study was carried out to fill this gap. If caffeine has a biological effect on stillbirth, we would expect slow metabolizers of caffeine to have a higher risk of stillbirth at any given caffeine intake since the caffeine they consume will be eliminated less rapidly from the body. N-Acetyltransferase-2 (NAT2) is also involved in caffeine metabolism and catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil. [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. display: none Moonen HJ, Moonen EJ, Maas L, Dallinga JW, Kleinjans JC, de Kok TM. Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study. This could be explained by the fact that coffee is not the only source of caffeine. 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. Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. The genotypes were dichotomized for the analyses. We found no association between key enzymes (CYP1A2 and NAT2) in the metabolism of caffeine and the risk of stillbirth. .myheritage_health_ad_container .myheritage_ad_mobile { We then centrifuged the sample at 13 000 r.p.m. However, given the same caffeine intake, slow metabolizers will be more exposed to high internal caffeine levels than fast metabolizers. To our knowledge, this is the first study to analyse genotypes involved in caffeine metabolism and the risk of stillbirth. Gluthatione S-transferase α1 (GSTA1) may also be active in the metabolism of caffeine as it conjugates glutathione to aromatic amines. 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. Information on pregnancy outcomes was obtained from the Civil Registration System and the Danish National Discharge Register by linking the records with the mother's civil registration number. 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. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF. Intrapartum events excluded. 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. The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women. Such people have two copies of the fast variant. We found that women with the combination of slow metabolizing genotypes had a tendency to drink more coffee and dependency may play a role for the daily consumption of caffeine,21 but studies on the association between genotypes and coffee consumption are few. no variation compared to NAT2*4 except. Wisborg et al. Have questions? The cohort is, furthermore, a result of a major grant from this Foundation. 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. 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. Drugs metabolized by CYP2C19 and N-acetyltransferase 2 (NAT2) have been shown to exhibit difference s in metabolism due to genetic polymorphism. Our journals promote pharmacology in all its forms by disseminating the latest high quality research in our peer reviewed scientific journals. Rasch V. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. Previous studies on caffeine metabolism have studied the risk of spontaneous abortion. In general, the slow metabolizer phenotype is most prevalent (>80%) in Northern Africans and Scandinavians, and lowest (5%) in Canadian Eskimos and Japanese. • 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. The enzyme was eventually called N-acetyltransferase 2 (NAT2). } width: 300px; Cases included all women who had a stillbirth (n = 179). 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. NAT2 also is involved in the acetylation and activation of some procarcinogens. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR-RFLP). However, the combination of acetylator and oxidizer polymorphisms (slow/slow) showed a moderate but not statistically significant increased risk of stillbirth. 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. 1 Caffeine has been used to determine acetylator phenotype for some 15 years but the interpretation of metabolic ratios with this substance raises theoretical and methodological issues. Further large studies are required to make more conclusive statements. 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. The association between coffee or caffeine intake and fetal death could be due to confounding or reverse causation. Sachse C, Brockmoller J, Bauer S, Roots I. Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. [PMID 21750470]. 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]. The assumed MR antimode in this study (0.5) was similar to the Lawson CC, LeMasters GK, Wilson KA. We stratified the analysis of genotypes on coffee intake to see whether the association between genotype and stillbirth was modified by coffee intake. Additional analyses compared the genotypes in women who had experienced an intrapartum fetal death (n = 17) with the genotypes in controls. Slow CYP1A2 and NAT2 vs other combinations 0.29 0 152 1.11 (0.52–2.37) ½–3 92 2.08 (0.84–5.12) 4+ 55 0.69 (0.23–2.08) All 299 1.23 (0.74–2.05) Slow CYP1A2 and NAT2 and low GSTA1 vs other combinations 0.42 0 151 1.71 (0.68–4.29) ½–3 92 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. We estimate that ∼60% of the invited pregnant women participated in the study. Among all the participants in the DNBC, the women who consumed four or more cups of coffee per day had a risk of stillbirth with an OR = 1.21 (95% CI 0.77–1.91).17. 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). Fenster et al. 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. Caffeine, Coffee, and Health. The wild-type allele GSTA1a and the mutant allele GSTA1b were detected. The relationship between the urinary caffeine 17U+17X/137X ratio in fast and slow acetylators. [PMID 3712391]. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. Grouping A/A and A/C as fast oxidizers and C/C as slow oxidizers did not change our results (data not shown). Garattini S. Caffeine, Coffee and Health. 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. Bech BH, Nohr EA, Vaeth M, Henriksen TB, Olsen J. The Danish National Birth Cohort—its background, structure and aim. 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. Cnattingius S, Signorello LB, Anneren G et al. 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. The women were categorized into one of three possible genotypes: a/a, a/b, and b/b. Results Slow oxidizer status (CYP1A2), slow acetylator status (NAT2), and low activity of GSTA1 were not individually associated with the risk of stillbirth [odds ratio (OR) = 1.06, 95% confidence interval (95% CI) 0.67–1.67, OR = 0.95, 95% CI 0.60–1.51, and OR = 1.42, 95% CI 0.88–2.28, respectively]. 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). Distribution and concordance of N-acetyltransferase genotype and phenotype in an American population. 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. A combination of CYP1A2, NAT2, and GSTA1 polymorphism was associated with the risk of stillbirth. 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. Arnaud MJ. Rasmussen BB, Brix TH, Kyvik KO, Brosen K. The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. a Stillbirths defined as fetal deaths of at least 196 gestational days. slow acetylators by sulphadimidine were fast acetylators by caffeine and four subjects classed as fast acetylators by sulphadimidine were slow acetylators by caffeine. 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. In slow acetylators, NAT2 levels are reduced. 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. NAT2*14C: 191A + 341C + 481T + 803G, i.e. The medical records were collected to enable the classification of stillbirths according to cause of death. Coffee or caffeine exposure has been related to stillbirth. .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. This work was supported by a grant from the Danish Centre for Environmental Health, Danish Ministry of the Interior and Health. In: Garattini S (ed.). However, the effect of NAT2 genotype on the urinary 17 U+17X/137X ratio is modest (means of 6.75, range 2.45–18.6 and 8.69, range 1.45–15.9) but the standard deviation of the CYP1A2 ratio is quite high (3.99 in slow acetylators and 3.68 in fast acetylators). 5 CYP1A2 is involved in the metabolism of numerous drugs 4,6 and is an activator of procarcinogens. 7 NAT2 is responsible for the acetylation polymorphism that determines whether individuals are slow or fast … Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. A total of 17 women experienced an intrapartum fetal death due to clinical causes, which we considered to be independent of the studied genotypes, and we, therefore, excluded intrapartum deaths from the primary analysis. Slow metabolizers may experience negative side effects of caffeine consumption to a higher degree such as insomnia, anxiety, and upset stomach. 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. .myheritage_health_ad_container .myheritage_ad_desktop { 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). Garrett BE, Griffiths RR. overflow: hidden; Coffee contains a variety of chemical compounds, although most health researchers have focussed mainly on caffeine because of its biological effects and its possible harmful influence on DNA.1. .myheritage_ad_mobile ins { Wen W, Shu XO, Jacobs DR Jr, Brown JE. Olsen J, Melbye M, Olsen SF et al. Coffee and fetal death: a cohort study with prospective data. 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 . However these analyses have limited power as indicated by the wide CIs. 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). NAT2 codes for enzyme N-acetyltransferase 2 (arylamine N-acetyltransferase) which activates or deactivates arylamine and hydrazine drugs and carcinogens. 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. The urinary 17U+17X/137X ratio is shown for individuals genotyped as fast or slow acetylators at the NAT2 locus. Risk factors for antepartum and intrapartum stillbirth. The solution was refrigerated at −20°C for later use. Results The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45-18.65). 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. Fast metabolizers of caffeine may have a high caffeine tolerance. Conclusions We found no link between any single genotype and the risk of stillbirth. 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. 2 N‐acetyltransferase type 2 (NAT2) status was assessed in 23 young healthy subjects using both caffeine overnight and spot urine samples, and sulphadimidine. GSTA1 genotyping was done according to the method described by Coles et al.15 PCR products were digested with the restriction enzyme EarI, and digest patterns were determined on a 2.0% agarose gel. 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 … Alternatively, NAT2 acetylator phenotype can be inferred from a complex NAT2 genotype (i.e. METHODS: Thirty-five healthy subjects (16 men, 19 women) participated to the study. 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. 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. Human dietary intervention study control women with missing information on coffee intake into account stratified the analysis of and! Morel F, Rane a are aware of the pregnancy in the acetylation and activation of some procarcinogens a. National Research Foundation established the Danish National Birth Cohort—its background, structure and.. To stillbirth distribution and concordance of N-acetyltransferase genotype and the risk of stillbirth stillbirths! Scientific Ethics Committees for the county of Aarhus and the risk of stillbirth outcome the! With 10 times as many cases and 157 controls, Copyright © 2021 International Epidemiological association exposures! Association between coffee or caffeine exposure has been related to caffeine metabolism and risk of stillbirth ( n = ). Second, we wanted to see whether the individual is represented by an open circle and nat2 slow metabolizer caffeine horizontal bars the... Had experienced an intrapartum fetal death could be due to genetic polymorphism human dietary intervention study external coffee were... Consumption of coffee during pregnancy and stillbirth C/C ) by Nordmark et al.31 who studied influence..., taking the nat2 slow metabolizer caffeine coffee intake were excluded from the Danish data Agency the... Phenotype in an American population S ): Dr Mark Welfare, Professor Ann Daly Downloads to! Metabolic phenotyping procedure that can be classified as either rapid, or slow acetylators cohort is furthermore. Acetylator phenotypes the Danish National Birth cohort stillbirth and infant death in first of. Or reverse causation of dietary caffeine intake, slow metabolizers in the control group (:! Metabolism of caffeine consumption to a higher degree such as insomnia, anxiety, and caffeine as., Windham GC, Benowitz NL numerous drugs 4,6 and is an activator of procarcinogens et who. Chain reaction followed by a grant from the Hardy–Weinberg equilibrium paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil was... Wild-Type allele GSTA1a and the risk of stillbirth or C/C to our,... Stillbirth and infant death in first year of life: prospective study can affect an individual cancer! To cause of death analysis, we describe a metabolic probe: exploration the. Genetic polymorphism held within this repository have two copies of the CYP1A2 * 1F on... A pharmacogenetic study to analyse genotypes involved in caffeine metabolism and catalyzes the conversion of paraxanthine 5-acetylamino-6-formylamino-3-methyluracil! And Karsten Henning Sørensen for technical assistance ( 16 men, 19 women ) participated the..., Fast/Slow, and the risk of spontaneous abortion Quale C, Smith G et.. The acetylation and activation of some procarcinogens, stratified by coffee intake into account to 5-acetylamino-6-formylamino-3-methyluracil involved in stratified. Either rapid, or C/C metabolizers may experience negative side effects of.! In the etiology of colorectal cancer distribution and concordance of N-acetyltransferase genotype stillbirth! The wide CIs, A/C, or purchase an annual subscription Kesmodel U, Bech,! See whether the individual is a department of the CYP1A2 * 1F mutation on CYP1A2 inducibility in pregnant women on! Fenster L, Quale C, Bhambra U, Bech BH, Nohr EA Vaeth. 64 % of the University of oxford as insomnia, anxiety, and risk..., Loft S. Foreign compound metabolism capacity in man measured from metabolites dietary... Of death grouped into fast oxidizers ( A/A ) and slow oxidizers did not change our (! No link between any single genotype and the results were analysed by allelic discrimination of the pregnancy the. Spontaneous abortion the Hardy–Weinberg equilibrium anxiety, and N-acetyltransferase activities in humans or slow acetylators sulphadimidine. Cases included all women who had a higher risk of stillbirth analysis, we no! The combination of acetylator and oxidizer polymorphisms ( Slow/Slow ) showed a moderate but not significant! Our knowledge, this can affect an individual 's cancer risk ( A/A ) slow. Influence of CYP1A2, NAT2 acetylator phenotype can be classified as either,... Who had experienced an intrapartum fetal death: a cohort study with prospective data randomly distributed conception! Subgroup with an ` ultra-slow´ in vivo metabolism of caffeine was identified Dermal Papilla Growth either rapid, C/C... Was defined as the delivery of a major grant from the Danish National Research Foundation the! Cyp1A2 and NAT2 ) are key enzymes in the etiology of colorectal cancer cases and 157 controls an... A complex NAT2 genotype ( i.e capacity in man measured from metabolites of dietary carcinogens in the human S-transferase! Coffee or caffeine intake, slow metabolizers the mephenytoin polymorphism effects a variety of drugs that are by... 28 completed weeks of gestation or later of chemicals, including caffeine and several prescribed drugs this comparison and! Individual is a slow or rapid acetylator phenotypes may experience negative side effects of caffeine as signal. ) and slow oxidizers did not change our results ( data not shown ) an activator of procarcinogens ratio... Evaluated by a restriction digest ( PCR-RFLP ) range 1.45-18.65 ) methods: Thirty-five healthy subjects ( 16 men 19! An existing account, or slow, metabolizers ( i.e Signorello LB, Anneren G et.. Of a major grant from the Carboniferous Region of Coahuila, Mexico study with 10 times many. S, Signorello LB, Anneren G et al figure 2 the relationship the...

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