Human acetyltransferase polymorphisms

Grant, Denis M.; Hughes, Nicola; Janezic, Susan A.; Goodfellow, Geoffrey H.; Chen, Hillary J; Gaedigk, Andrea; Yu, Violeta; Grewal, Ranbir

doi:10.1016/s0027-5107(97)00026-2

Cited by 233 publications

(139 citation statements)

References 26 publications

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“…NAT2 allozymes encoded by alleles with base substitutions at positions 191, 590, or 857 were found to be significantly more unstable in bacterial expression systems than the wild-type protein. 52,61,64 However, in these studies the amount of immunodetectable NAT2 protein was not different upon expression of the variant and wild-type alleles. This is in contrast to the earlier observations by Grant and coworkers 57 who showed that liver NAT2 content was markedly reduced in slow acetylators, suggesting that the artificial environment of bacterial expression systems may not accurately reflect what occurs in mammalian cells with regard to protein degradation.…”

Section: Human Natsmentioning

confidence: 56%

“…To date, 29 different NAT2 alleles have been detected in human populations (Table 1; reviewed in 15,24,52 ). Each of the variant alleles is comprised of between one and four nucleotide substitutions, of which 13 have been identified, located in the protein encoding region of the gene.…”

Section: Human Natsmentioning

confidence: 99%

“…It wasn't until 1993 when Vatsis and Weber 73 first reported the existence of several allelic variations at the NAT1 locus that interest in the NAT1 gene was aroused, marking the beginning of a systematic survey of NAT1 genotypes. To date, 26 different NAT1 alleles have been detected in human populations (Table 2; reviewed in 15,24,52 ), however, only a small number have been shown to alter phenotype in vivo. Hughes and coworkers 17 used PAS as a probe drug to phenotype a population for NAT1 activity.…”

Section: Human Nat1 Allelesmentioning

confidence: 99%

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Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.

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Section: Human Natsmentioning

confidence: 56%

Section: Human Natsmentioning

confidence: 99%

Section: Human Nat1 Allelesmentioning

confidence: 99%

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Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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“…NAT1 was sequenced using forward nested primers N393F (5 0 -GTGGC AGCCT CTGGA GT) and N1208F (5 0 -GACTC TGAGT GAGGA AGAAA TA). Genotypes were assigned according to the DNA sequences for the known NAT1 alleles reported by Deitz et al 24 and Grant et al 15 (summarized by Hein at www.louisville.edu/medschool/pharmacology/NAT1.html). Eight NAT1 acetylator alleles (NAT1 * 3, NAT1 * 4, NAT1 * 10, NAT1 * 11, NAT1 * 14, NAT1 * 15, NAT1 * 16, and NAT1 * 18) and 14 genotypes were identified.…”

Section: Genetic Data Collectionmentioning

confidence: 99%

“…13 NAT1 and NAT2 genotypes are polymorphic in humans and they are generally described as rapid and slow acetylators. 14,15 Since heterocyclic amines cannot be N-acetylated but can be activated by Oacetylation following N-hydroxylation, 13 humans with rapid acetylation phenotypes may be more prone to carcinogenic influence of heterocyclic amines. Human prostate epithelial cells express NATs and they are capable of activating heterocyclic amines.…”

Section: Introductionmentioning

confidence: 99%

Heterocyclic amines and genotype of N-acetyltransferases as risk factors for prostate cancer

Rovito

Morse

Spinek

et al. 2005

Prostate Cancer Prostatic Dis

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A variety of carcinogenic heterocyclic amines are produced during the cooking of meat at high temperatures. These carcinogens are metabolized by Nacetyltransferases (NAT), which are polymorphic in the population. This study examined associations between prostate cancer (PCa) and the consumption of different kinds of meat, heterocyclic amine intake and NAT genotypes. PCa patients and controls were recruited in the Syracuse, NY area. Levels of meat and heterocyclic amine intakes were determined from validated surveys and NAT genotypes were determined by the sequences of PCR-amplified DNA from buccal swabs. A total of 152 cases and 161 controls were eligible for analysis. There was an association between PCa and history of PCa in the first-degree blood relatives (OR ¼ 4.59, 95% CI 2.21-9.70), and family history of bladder cancer (Po0.02). However, there was no association with the history of other cancers. There was no association between PCa and either 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) intake, or NAT1 and NAT2 genotypes. However, there was a trend of association with MeIQx and with rapid NAT2 and NAT1 * 10 in combination with PhIP. A new NAT1 allele with a frequency of one out of 544 chromosomes was found in the Caucasian subjects.

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SNPs: Single Nucleotide Polymorphisms and Pharmacogenomics—Individually Designed Drug Therapy

Puckett¹,

Terra²,

Walker³

2003

Burger's Medicinal Chemistry and Drug Discovery

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Pharmacogenomics is a rapidly expanding field aimed at understanding interpatient variability in drug response through the exploration and investigation of the human genome. It is an incontrovertible fact that large interpatient variability exists in response to medications. Variation in response has existed as long as medications have been used for the prevention and treatment of disease. In many ways, the field of pharmacogenomics began serendipitously in the 1950s after seminal observations describing variability in response to medications. Examples included peripheral neuropathy from isoniazid among slow acetylator, prolonged apnea from succinylcholine caused by pseudocholinesterase deficiency, and severe hypotension from debrisoquine among cytochrome P450 (CYP) 2D6 poor metabolizers. For the next 40 years, pharmacogenetic studies focused almost exclusively on the etiologies of altered variability in pharmacokinetic responses to medications. As we entered the 1990s, pharmacogenomic studies began to include studies that examined pharmacodynamic variability in drug response. Now instead of examining only differences in drug metabolizing enzymes, scientists began to focus on genes that encode drug transporters, drug targets, and ion channels. The ultimate goal of pharmacogenomics is to be able to accurately predict, based on an individual's genomic information, which medications will provide the greatest benefit with the least harm, thus transforming medicine into an era of personalized therapeutics. This chapter provides a review of pharmacogenomics and how single nucleotide polymorphisms may impact pharmacotherapy and drug discovery. The chapter further explores the abundant recent literature as well as provides insight into some of the issues, limitations, and ethical considerations of pharmacogenomics.

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Human acetyltransferase polymorphisms

Cited by 233 publications

References 26 publications

Pharmacogenetics of the arylamine N-acetyltransferases

Pharmacogenetics of the arylamine N-acetyltransferases

Heterocyclic amines and genotype of N-acetyltransferases as risk factors for prostate cancer

SNPs: Single Nucleotide Polymorphisms and Pharmacogenomics—Individually Designed Drug Therapy

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