title: Systemic functional expression of N-acetyltransferase polymorphism in the F344 Nat2 congenic rat.
abstract: Rat lines congenic for the rat N-acetyltransferase 2 [(RAT)Nat2] gene were constructed and characterized. F344 (homozygous Nat2 rapid) males were mated to Wistar Kyoto (homozygous Nat2 slow) females to produce heterozygous F1. F1 females were then backcrossed to F344 males. Heterozygous acetylator female progeny from this and each successive backcross were identified by rat Nat2 genotyping and mated with F344 rapid acetylator males. After 10 generations of backcross mating, heterozygous acetylator brother/sister progeny were mated to produce the homozygous rapid and slow acetylator Nat2 congenic rat lines. p-Aminobenzoic acid (selective for rat NAT2) and 4-aminobiphenyl N-acetyltransferase activities were expressed in all tissues examined (liver, lung, esophagus, stomach, small intestine, colon, pancreas, kidney, skin, leukocytes, and urinary bladder in male and female rats and in breast of female and prostate of male rats). NAT2 expression in rat extrahepatic tissues was much higher than that in liver. In each tissue, activities were Nat2-genotype-dependent, with the highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators, and lowest in homozygous slow acetylators. Sulfamethazine (selective for rat NAT1) N-acetyltransferase activities were observed in all tissues examined in both male and female rats except for breast (females), bladder, and leukocytes. In each tissue, the activity was Nat2 genotype-independent, with similar levels in homozygous rapid, heterozygous, and homozygous slow acetylators. These congenic rat lines are useful for investigating the role of NAT2 genetic polymorphisms in susceptibility to cancers related to arylamine carcinogen exposures.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA. d.hein@louisville.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: Jean
authors.initials: J
authors.lastname: Bendaly
authors.forename: Jason R
authors.initials: JR
authors.lastname: Neale
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
mesh_terms: D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000611:Aminobiphenyl Compounds / Q000378:metabolism; D000818:Animals; D020296:Animals, Congenic; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006579:Heterozygote; D006720:Homozygote; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D012727:Sex Characteristics; D013418:Sulfamethazine / Q000378:metabolism
chemical_list: D000611:Aminobiphenyl Compounds; D007527:Isoenzymes; C006757:4-biphenylamine; D013418:Sulfamethazine; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C541077:NAT2 protein, rat; D010129:4-Aminobenzoic Acid
references.citation: Toxicol Appl Pharmacol. 1999 May 1;156(3):187-94
references.pmid: 10222311
references.citation: Drug Metab Dispos. 1991 Sep-Oct;19(5):933-7
references.pmid: 1686239
references.citation: Arch Toxicol. 1992;66(2):112-7
references.pmid: 1605725
references.citation: J Pharmacol Exp Ther. 2006 Jan;316(1):289-94
references.pmid: 16192314
references.citation: Carcinogenesis. 1993 Aug;14(8):1633-8
references.pmid: 8353847
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 May;9(5):529-32
references.pmid: 10815700
references.citation: Toxicol Appl Pharmacol. 1997 Nov;147(1):56-62
references.pmid: 9356307
references.citation: Drug Metab Dispos. 2007 Jul;35(7):1064-70
references.pmid: 17403913
references.citation: Toxicol Appl Pharmacol. 1994 Jan;124(1):16-24
references.pmid: 8291057
references.citation: Pharmacogenet Genomics. 2006 Jul;16(7):515-25
references.pmid: 16788383
references.citation: Pharmacogenetics. 2003 Jul;13(7):399-407
references.pmid: 12835615
references.citation: Drug Metab Dispos. 2007 May;35(5):721-7
references.pmid: 17287389
references.citation: J Pharmacol Exp Ther. 1991 Nov;259(2):699-704
references.pmid: 1941618
references.citation: Drug Metab Dispos. 1993 Nov-Dec;21(6):1057-63
references.pmid: 7905384
references.citation: Biochem Pharmacol. 1973 Jul 1;22(13):1581-8
references.pmid: 4729805
references.citation: Drug Metab Dispos. 2008 Dec;36(12):2445-51
references.pmid: 18799802
references.citation: Drug Metab Rev. 2005;37(3):511-64
references.pmid: 16257833
references.citation: Exp Neurol. 2004 May;187(1):199-202
references.pmid: 15081601
references.citation: Drug Metab Dispos. 2006 Oct;34(10):1697-702
references.pmid: 16815960
references.citation: Cancer Lett. 2000 Feb 28;149(1-2):53-60
references.pmid: 10737708
references.citation: Gene. 1994 Mar 25;140(2):247-9
references.pmid: 8144033
references.citation: J Pharmacol Exp Ther. 1999 Jul;290(1):182-7
references.pmid: 10381774
references.citation: Pharmacogenetics. 1995 Aug;5(4):247-51
references.pmid: 8528272
references.citation: Jpn J Cancer Res. 1985 Jul;76(7):570-6
references.pmid: 3928552
references.citation: Mol Pharmacol. 1991 Aug;40(2):218-27
references.pmid: 1875909
references.citation: Mol Carcinog. 2006 Apr;45(4):230-8
references.pmid: 16482518
references.citation: Carcinogenesis. 2003 Apr;24(4):719-25
references.pmid: 12727801
references.citation: Mutat Res. 2002 Sep 30;506-507:65-77
references.pmid: 12351146
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):15-26
references.pmid: 18187392
references.citation: Arch Biochem Biophys. 2007 Aug 15;464(2):169-75
references.pmid: 17601487
references.citation: Pharmacogenetics. 1997 Apr;7(2):121-30
references.pmid: 9170149
references.citation: Oncogene. 2006 Mar 13;25(11):1649-58
references.pmid: 16550165
references.citation: Rapid Commun Mass Spectrom. 2003;17(18):2125-32
references.pmid: 12955743
references.citation: Toxicol Sci. 2007 Oct;99(2):413-21
references.pmid: 17567587
references.citation: Mol Pharmacol. 2003 Jul;64(1):170-9
references.pmid: 12815173
references.citation: Pharmacogenetics. 1994 Apr;4(2):91-100
references.pmid: 7915937
references.citation: Food Chem Toxicol. 1999 Feb-Mar;37(2-3):125-34
references.pmid: 10227736
references.citation: Biochem Pharmacol. 1996 Nov 22;52(10):1613-20
references.pmid: 8937477
references.citation: J Pharmacol Exp Ther. 1991 Jul 1;258(1):232-6
references.pmid: 2072298
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):369-75
references.pmid: 16829624
references.citation: Drug Metab Dispos. 1993 Sep-Oct;21(5):965-6
references.pmid: 7902264
references.citation: Nucleic Acids Res. 1989 May 11;17(9):3589
references.pmid: 2726493
references.citation: Pharmacogenetics. 1991 Oct;1(1):50-7
references.pmid: 1844823
references.citation: Drug Metab Dispos. 1995 Feb;23(2):295-7
references.pmid: 7736928
references.citation: Biochem J. 1973 Mar;132(3):519-26
references.pmid: 4724587
references.citation: Environ Mol Mutagen. 2002;39(2-3):184-92
references.pmid: 11921188
references.citation: J Pharmacol Exp Ther. 2006 Nov;319(2):724-8
references.pmid: 16857729
references.citation: Drug Metab Dispos. 2007 Sep;35(9):1649-56
references.pmid: 17591675
references.citation: Biomarkers. 2008 Feb;13(1):106-18
references.pmid: 17896208