Effects of Heredity on Response to Drugs and Environmental Chemicals:  Construction of Rodent Models

Levy, Gerald N.; Rodgers, Lourdes; Weber, Wendell W.

doi:10.1021/tx960082y

Cited by 3 publications

(3 citation statements)

References 39 publications

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“…In these rodents there is evidence for a difference in expression of individual NAT isozymes along the length of the intestine. Therefore the understanding of the expression of human NAT isoenzymes along the length of the intestine together with comparison of the substrate specificities of the NAT isoenzymes of different species will allow the establishment of sensible models for understanding human colon carcinogenesis35 and may serve as an additional means of validating animal models of inflammatory bowel disease 36…”

Section: Discussionmentioning

confidence: 99%

Expression of arylamine N-acetyltransferase in human intestine

Hickman

Pope

Patil

et al. 1998

Gut

137

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Background-Arylamine N-acetyltransferases in humans (NAT1 and NAT2) catalyse the acetylation of arylamines including food derived heterocyclic arylamine carcinogens. Other substrates include the sulphonamide 5-aminosalicylic acid (5-ASA), which is an NAT1 specific substrate; N-acetylation of 5-ASA is a major route of metabolism. NAT1 and NAT2 are both polymorphic. Aims-To investigate NAT expression in apparently healthy human intestines in order to understand the possible role of NAT in colorectal cancer and in the therapeutic response to 5-ASA. Methods-The intestines of four organ donors were divided into eight sections. DNA was prepared for genotyping NAT1 and NAT2 and enzymic activities of NAT1 and NAT2 were determined in cytosols prepared from each section. Tissue was fixed for immunohistochemistry with specific NAT antibodies. Western blotting was carried out on all samples of cytosol and on homogenates of separated muscle and villi after microdissection. Results-NAT1 activity of all cytosols was greater than NAT2 activity. NAT1 and NAT2 activities correlated with the genotypes of NAT1 and NAT2 and with the levels of NAT1 staining determined by western blotting. The ratio of NAT1:NAT2 activities showed interindividual variations from 2 to 70. NAT1 antigenic activity was greater in villi than in muscle. NAT1 was detected along the length of the villi in the small intestine. In colon samples there was less NAT1 at the base of the crypts with intense staining at the tips. Conclusions-The interindividual variation in NAT1 and NAT2 in the colon could aVect how individuals respond to exposure to specific NAT substrates including carcinogens and 5-ASA. (Gut 1998;42:402-409)

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Section: Discussionmentioning

confidence: 99%

Expression of arylamine N-acetyltransferase in human intestine

Hickman

Pope

Patil

et al. 1998

Gut

137

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“…Rodent models of the human NAT2 acetylation polymorphism have been reviewed (Levy et al, 1996;Hein et al, 1997Hein et al, , 2000Boukouvala and Fakis, 2005). Three mouse Nat genes with 870-base pair intronless open reading frames were identified and designated as Nat1, Nat2, and Nat3 (Martell et al, 1992;Kelly and Sim, 1994).…”

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confidence: 99%

“…Various mouse models focusing on Nat2 have been reviewed (Levy et al, 1996;Boukouvala and Fakis, 2005). Among these various models, a murine Nat2 knockout (KO) model was created on a C57B1/6 background by the insertion of an ablative cassette into the Nat2 coding region, resulting in a nonfunctional gene product (Cornish et al, 2003).…”

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confidence: 99%

N-Acetyltransferase (Nat) 1 and 2 Expression in Nat2 Knockout Mice

Loehle

Cornish²,

Wakefield³

et al. 2006

J Pharmacol Exp Ther

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Arylamine N-acetyltransferases (Nat) 1 and 2 catalyze the Nacetylation of aromatic amine and hydrazine drugs and carcinogens. After N-hydroxylation, they also catalyze the metabolic activation of N-hydroxy-arylamines via O-acetylation. Functional characterization of mouse Nat1 and Nat2 was investigated in an Nat2 knockout (KO) model and compared with the wild-type (WT) strain. Nat1-and Nat2-specific mRNA, determined by quantitative real-time polymerase chain reaction, was detected in all tissues examined and did not differ significantly (p Ͼ 0.05) between Nat2 KO and WT mice. Nat1 catalytic activity was present in all tissues examined and did not differ significantly (p Ͼ 0.05) between the Nat2 KO and WT mice. In contrast, Nat2 catalytic activity was present in all tissues examined from male WT mice but was below the limit of detection in all tissues of Nat2 KO mice. N-acetyltransferase activity toward the aromatic amine carcinogen 4-aminobiphenyl and O-acetyltransferase activity toward its proximate metabolite N-hydroxy-4-aminobiphenyl were both present in tissue cytosols of WT mice but were undetectable in Nat2 KO mice. Nat2 protein was readily detectable in liver cytosols of WT mice but not in liver cytosols from Nat2 KO mice. Since the reductions in Nat2 activity correlated with reductions in Nat2-specific protein but not mRNA, these results strongly suggest that insertion of the LacZ ablation cassette eliminated Nat2 protein and catalytic activity via disruption of the Nat2 protein, without significantly affecting transcription rates or transcript stability. The Nat2 KO model will be useful in future studies to assess the role of Nat2 in arylamine carcinogenesis.

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The pharmacogenetics of NAT: structural aspects

Pompeo¹,

Brooke²,

Kawamura³

et al. 2002

pgs

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Arylamine N-acetyltransferases (NATs) catalyze the transfer of an acetyl group from acetyl-CoA to arylhydrazines and to arylamine drugs and carcinogens or to their N-hydroxylated metabolites. NAT plays an important role in detoxification and metabolic activation of xenobiotics and was first identified as the enzyme responsible for inactivation of the antitubercular drug isoniazid, an arylhydrazine. The rate of inactivation was polymorphically distributed in the population: the first example of interindividual pharmacogenetic variation. Polymorphism in NAT activity is primarily due to single nucleotide polymorphisms (SNPs) in the coding region of NAT genes. NAT enzymes are widely distributed in eukaryotes and genome sequences have revealed many homologous members of this enzyme family in prokaryotes. The structures of S almonella typhimurium and Mycobacterium smegmatis NATs have been determined, revealing a unique fold in which a catalytic triad (Cys-His-Asp) forms the active site. Determination of prokaryotic and eukaryotic NAT structures could lead to a better understanding of their role in xenobiotics and endogenous metabolism.

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Effects of Heredity on Response to Drugs and Environmental Chemicals: Construction of Rodent Models

Cited by 3 publications

References 39 publications

Expression of arylamine N-acetyltransferase in human intestine

Expression of arylamine N-acetyltransferase in human intestine

N-Acetyltransferase (Nat) 1 and 2 Expression in Nat2 Knockout Mice

The pharmacogenetics of NAT: structural aspects

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