N-acetylation pharmacogenetics: a gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits.

Blum, Martin; Grant, Denis M.; Demierre, Anne; Meyer, Urs

doi:10.1073/pnas.86.23.9554

Cited by 44 publications

(22 citation statements)

References 20 publications

(17 reference statements)

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“…Several different mechanisms are responsible for NAT2 polymorphisms in non-human species. The molecular basis for slow acetylator phenotype is NAT2 gene deletion in the rabbit (Blum et al, 1989), a nonsense single-nucleotide polymorphism (SNP) yielding a truncated NAT2 enzyme in the Syrian hamster (Ferguson et al, 1994(Ferguson et al, , 1996Nagata et al, 1994), and missense SNP(s) in the mouse and rat . Both NAT1 and NAT2 have been identified and partially purified from Syrian hamster liver Smith and Hanna, 1986;Trinidad et al, 1989;Ozawa et al, 1990), intestine (Smith and Hanna, 1986), colon (Hein et al, 1993a), prostate and urinary bladder cytosols.…”

Section: Animal Modelsmentioning

confidence: 99%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

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Section: Animal Modelsmentioning

confidence: 99%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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“…All genes have an intronless open reading frame and polymorphism in NAT activity has been described in strains of rabbits, 44 hamsters 45 and rats, 46 all of which possess two Nat genes. Upstream non-coding exons have also been described for the rabbit Nat genes.…”

Section: Gene Localisation Structure and Expressionmentioning

confidence: 99%

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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“…Immunoreaction on Western blots used a polyclonal rabbit antiserum raised against purified human NAT2 (8). The serum was prepurified on nitrocellulose strips containing purified rabbit NAT2 (23,24). Blot intensities of NAT2-specific protein bands at 31 kDa were quantified by using a Camag (Muttenz, Switzerland) TLC scanner in the transmission mode.…”

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confidence: 99%

“…EcoRI fragments (1.9 kb) containing NAT2 coding exons were subcloned in the vector p91023 (B) (22) and transiently expressed in COS-1 cells as described (23).…”

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confidence: 99%

Molecular mechanism of slow acetylation of drugs and carcinogens in humans.

Blum

Demierre

Grant

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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313

182

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The acetylation polymorphism is one of the most common genetic variations in the transformation of drugs and chemicals. More than 50% of individuals in Caucasian populations are homozygous for a recessive trait and are of the "slow acetylator" phenotype. They are less efficient than "rapid acetylators" in the metabolism of numerous drugs and environmental and industrial chemicals. The acetylation polymorphism is associated with an increased risk of drug toxicity and with an increased frequency of certain cancers. We report the identification of the primary mutations in two alleles of the gene for the N-acetyltransferase (NAT; acetyl-CoA:arylamine N-acetyltransferase, EC 2.3.1.5) isozyme NAT2 associated with slow acetylation. These alleles, Ml and M2, account for more than 90% of slow acetylator alleles in the European population we have studied. Ml and M2 were identified by restriction fragment length polymorphisms with Kpn I and Msp I and subsequently cloned and sequenced. Ml and M2 each are characterized by a combination of two different point mutations, one causing an amino acid substitution (Ile-113 -* Thr in Ml, Gin in M2), the other being silent (C 481 -+ T in Ml, C 282 T in M2). Functional expression of Ml and M2 and of chimeric gene constructs between mutant and wild-type NAT2 in COS-1 cells suggests that Ml causes a decrease of NAT2 protein in the liver by defective translation, whereas M2 produces an unstable enzyme. On the basis of the mutations described here and a rare mutant allele (M3) reported recently, we have developed a simple DNA amplification assay that allows the predictive genotyping of more than 95% of slow and rapid acetylator alleles and the identification of individuals at risk.The acetylation polymorphism is one of the most common inherited variations in the biotransformation of drugs and chemicals. Its association with drug toxicity and an increased risk to develop certain cancers has made it one of the oldest and best-studied examples of a pharmacogenetic condition (1-3). Forty to 70% of Caucasians in Europe and North America are of the "slow acetylator" phenotype and are less efficient than "rapid acetylators" in the metabolism of numerous drugs and chemicals containing primary aromatic amine or hydrazine groups. These include agents such as isoniazid, sulfamethazine (SMZ) and other sulfonamides, procainamide, hydralazine, dapsone, and caffeine, as well as several chemicals with carcinogenic potential such as benzidine, 2-aminofluorene, and f-naphthylamine, present in dyes, antioxidants, pesticides, and explosives (2-4). Highly mutagenic and carcinogenic arylamines also are generated during cooking of food (5). Slow acetylators are at higher risk to develop bladder cancer (1-4), whereas rapid acetylators are at higher risk for colorectal cancer (6).In previous studies, we have shown that slow acetylators have a quantitative decrease in their liver of a cytosolic arylamine N-acetyltransferase (NAT; acetyl-CoA:arylamine N-acetyltransferase, EC 2.3.1.5) (7). This enzyme was p...

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N-acetylation pharmacogenetics: a gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits.

Cited by 44 publications

References 20 publications

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

Pharmacogenetics of the arylamine N-acetyltransferases

Molecular mechanism of slow acetylation of drugs and carcinogens in humans.

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