Multiple <i>N</i>-acetyltransferases and drug metabolism. Tissue distribution, characterization and significance of mammalian <i>N</i>-acetyltransferase

Hearse, D. J.; Weber, Wendell W.

doi:10.1042/bj1320519

Cited by 131 publications

(36 citation statements)

References 7 publications

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“…This hypothesis derives from studies in the rabbit model where N-acetyltransferase activities reflected the NAT2 genetic polymorphism in the liver and gut, but not in other tissue cytosols, suggesting either absence or a much smaller contribution of rabbit NAT2 in these other tissues (Hearse and Weber, 1973). Furthermore, a subsequent study reported that the rapid/slow NAT2 ratio for both sulfamethazine Nacetyltransferase and N-hydroxy-ABP O-acetyltransferase activities were much higher in rabbit liver than small and large intestine (Ilett et al, 1991).…”

Section: Phenotypic Expression Of the Nat2 Polymorphismmentioning

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: Phenotypic Expression Of the Nat2 Polymorphismmentioning

confidence: 99%

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

2006

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“…The hNAT1/mNAT2 isoform is expressed in a wide range of tissues, including liver, colon, small intestine, placenta, lungs, kidney, bladder, blood, and skin (11,18,32,59). In contrast, hNAT2/mNAT1 is expressed mainly in liver, small intestine, and colon (13,14,29,32,35).…”

mentioning

confidence: 99%

Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Ramírez-Alcántara

Montrose

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ramírez-Alcántara V, Montrose MH. Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2. Am J Physiol Gastrointest Liver Physiol 306: G1002-G1010, 2014. First published April 17, 2014 doi:10.1152/ajpgi.00389.2013.-Pharmacotherapy based on 5-aminosalicylic acid (5-ASA) is a preferred treatment for ulcerative colitis, but variable patient response to this therapy is observed. Inflammation can affect therapeutic outcomes by regulating the expression and activity of drug-metabolizing enzymes; its effect on 5-ASA metabolism by the colonic arylamine N-acetyltransferase (NAT) enzyme isoforms is not firmly established. We examined if inflammation affects the capacity for colonic 5-ASA metabolism and NAT enzyme expression. 5-ASA metabolism by colonic mucosal homogenates was directly measured with a novel fluorimetric rate assay. 5-ASA metabolism reported by the assay was dependent on Ac-CoA, inhibited by alternative NAT substrates (isoniazid, p-aminobenzoylglutamate), and saturable with Km (5-ASA) ϭ 5.8 M. A mouse model of acute dextran sulfate sodium (DSS) colitis caused pronounced inflammation in central and distal colon, and modest inflammation of proximal colon, defined by myeloperoxidase activity and histology. DSS colitis reduced capacity for 5-ASA metabolism in central and distal colon segments by 52 and 51%, respectively. Use of selective substrates of NAT isoforms to inhibit 5-ASA metabolism suggested that mNAT2 mediated 5-ASA metabolism in normal and colitis conditions. Western blot and real-time RT-PCR identified that proximal and distal mucosa had a decreased mNAT2 protein-to-mRNA ratio after DSS. In conclusion, an acute colonic inflammation impairs the expression and function of mNAT2 enzyme, thereby diminishing the capacity for 5-ASA metabolism by colonic mucosa. drug metabolism; fluorescence; dextran sulfate sodium; myeloperoxidase; kinetics; enzymatic assay; inflammatory bowel disease; enzyme isoform THE TWO MAJOR INFLAMMATORY bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease, afflict 1.4 million individuals in the United States (USA) and 2.2 million in Europe (42). To induce and maintain mucosal healing of the colonic mucosa, the major goal of UC therapy is to reduce or eliminate colonic inflammation. For mild to moderate inflammation, therapy based on the nonsteroidal anti-inflammatory compound 5-aminosalicylic acid (5-ASA) is frequently prescribed. In information compiled by the National Institutes of Health from the 2004 Verispan database of prescriptions filled at retail pharmacies in the USA, 5-ASA or its prodrugs accounted for 44% of Crohn's disease prescriptions and 81% of UC prescriptions (23). It is not well understood how 5-ASA induces its antiinflammatory effect on colonic mucosa, but multiple mechanisms have been proposed, including inhibition of intestinal macrophage chemotaxis (47), inhibition of proinflammatory cytokine release (25), inhibition of cyclooxygenase and prostaglandin pathways (28), inhibition of nuclear fa...

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“…e., damage to DNA (28)-by substrates of N-acetyltransferase could be affected by the amount of acetylation. In order to investigate this possibility, we developed a model system that permitted measurement of both N-acetyltransferase activity and DNA damage in the same cells, using hepatocytes, which represent a major tissue of acetylation (29)(30)(31)(32), derived from rapid and slow acetylator rabbits.…”

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confidence: 99%

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

McQueen

Maslansky

Glowinski

et al. 1982

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

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The relationship between acetylation rates of rabbit hepatocytes and their susceptibility to genotoxicity by DNAdamaging chemicals that undergo N-acetylation was studied in primary cultures of hepatocytes from New Zealand White rabbits that have a genetically determined difference in acetylation rates. Hepatocytes from rapid and slow acetylator rabbits maintained in culture the difference in acetylation rates that existed in viva DNA repair, an index of DNA damage, was produced by hydralazine in hepatocytes from slow acetylator rabbits but not in those from rapid acetylators. In contrast to these results, hepatocytes from rapid acetylators were more sensitive than those from slow acetylators to toxicity from the carcinogen 2-aminofluorene and displayed greater amounts of DNA repair. The amount of DNA repair measured with either chemical was dose dependent. These phenotype-dependent differences in the genotoxicity of two DNAdamaging chemicals provide evidence for the role of the acetylation polymorphism as a factor in determining susceptibility to toxicity, and perhaps carcinogenicity, of these chemicals. N-Acetylation rates of xenobiotics are under polymorphic genetic control in both humans and rabbits, resulting in individuals being either rapid or slow acetylators (1-5). This trait has been linked to toxicity and damage to DNA by chemicals of the aromatic amine or hydrazine type (6). For example, slow acetylator individuals are more likely than rapid acetylators to develop drug-related systemic lupus erythematosus (6-8). Individuals that develop this reaction have antinuclear antibodies as well as antibodies to DNA and nucleoproteins (6)(7)(8)(9)(10)(11)(12)(13). In vitro studies have also demonstrated interaction of systemic lupus erythematosus-inducing drugs with DNA (11,14,15).In the metabolism ofxenobiotics, N-acetylation is a step that can be followed by reactions such as N-hydroxylation and esterification, resulting in the generation of reactive metabolites that undergo covalent binding with cellular macromolecules, including DNA (16,17). Chemicals that can be acetylated and that also form covalent adducts with DNA include procainamide (18,19), isoniazid (20), and hydralazine (15), as well as the aromatic amine carcinogens, benzidine (21, 22), 2-aminofluorene, and 4-aminobiphenyl (23). Adduct formation by chemicals can be mediated by the enzymatic removal of the N-acetyl moiety (24,25), and evidence in the rabbit suggests that this reaction and the initial acetylation step are properties of the same enzyme (26).Because a difference in the acetylation rate can alter the proportion ofspecific metabolites that are formed (27), it is possible that genotoxicity-i. e., damage to DNA (28)-by substrates of N-acetyltransferase could be affected by the amount of acetylation. In order to investigate this possibility, we developed a model system that permitted measurement of both N-acetyltransferase activity and DNA damage in the same cells, using hepatocytes, which represent a major tissue of acetylation (...

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Multiple N-acetyltransferases and drug metabolism. Tissue distribution, characterization and significance of mammalian N-acetyltransferase

Cited by 131 publications

References 7 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

Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

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