N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. [PMID 20739907], The proportion of slow and rapid metabolizers is known to differ between different ethnic populations. In turn, this can affect an individual's cancer risk. 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. Additional analyses compared the genotypes in women who had experienced an intrapartum fetal death (n = 17) with the genotypes in controls. 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). Drug Interactions in Slow Metabolizers The mephenytoin polymorphism effects a variety of drugs that are metabolized by CYP2C19. 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. We used STATA (Version 8.0 SE) for all statistical analyses. [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. 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. .myheritage_health_ad_container .myheritage_ad_desktop { The Scientific Ethics Committees for the county of Aarhus and the Danish Data Agency approved the study. Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. Moonen HJ, Moonen EJ, Maas L, Dallinga JW, Kleinjans JC, de Kok TM. @media (max-width: 479px) { 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 … Caffeine is also found in tea, cocoa, cola, chocolate, and certain medications. 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). 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. 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. 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). In general, slow metabolizers have higher rates of certain types of cancer and are more susceptible to side effects from chemicals metabolized by NAT2. The wild-type allele GSTA1a and the mutant allele GSTA1b were detected. for 1 min and transferred the supernatant (∼150 μl) to a clean tube, adding 5–15 μl DNA solution to the PCR mix. To our knowledge, this is the first study to analyse genotypes involved in caffeine metabolism and the risk of stillbirth. Little RE, Weinberg CR. We randomly sampled a similar number of control women with a singleton live birth. However, the combination of acetylator and oxidizer polymorphisms (slow/slow) showed a moderate but not statistically significant increased risk of stillbirth. 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. 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. In the stratified analysis, we found no support for an interaction between genotypes and coffee intake. 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). We stratified the analysis of genotypes on coffee intake to see whether the association between genotype and stillbirth was modified by coffee intake. Fenster et al. Caffeine may be causally related to stillbirth, but larger studies using Mendelian randomization are needed to verify this. 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. 5 CYP1A2 is involved in the metabolism of numerous drugs 4,6 and is an activator of procarcinogens. Rasch V. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. A study with 10 times as many cases and controls may be needed to explore these interactions. Resident Physician in Cardio-Thoracic and Vascular Surgery,     Slow NAT2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological Association. [PMID 16416399]. This was also found by Nordmark et al.31 who studied the influence of CYP1A2 genotype on the CYP1A2 activity in pregnant women. Such people have two copies of the fast variant. 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. 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. Coffee consumption is related to many other lifestyle factors that cannot fully be adjusted for. Caffeine is considered to be a fetotoxic compound. 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. Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. Risk factors for antepartum and intrapartum stillbirth. The women were then categorized into one of three possible genotypes: Fast/Fast, Fast/Slow, and Slow/Slow. Bech BH, Nohr EA, Vaeth M, Henriksen TB, Olsen J. 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. 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