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Role of N-acetyltransferase 2 polymo...

Metry, Kristin J.

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Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens./
Author:	Metry, Kristin J.
Description:	154 p.
Notes:	Adviser: David W. Hein.
Contained By:	Dissertation Abstracts International68-05B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3267099
ISBN:	9780549052906

Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens.
Metry, Kristin J.

Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens. - 154 p.

Adviser: David W. Hein.

Thesis (Ph.D.)--University of Louisville, 2007.

The interaction between genes and environment may predict cancer risk, and therefore polymorphisms in N-acetyltransferase 2 (NAT2), an important enzyme in xenobiotic metabolism, may play an important role in cancer susceptibility. Humans are exposed to heterocyclic amine carcinogens such as 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx) 2-amino-3-methylimidazo [4,5-f] quinoline (IQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), as well as aromatic amines, such as 4-aminobiphenyl (ABP) and 2-aminofluorene (AF). Bioactivation includes N-hydroxylation catalyzed by CYP1A2 followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). To better understand the role of NAT2 genetic polymorphism in aromatic and heterocyclic amine-induced mutagenesis and DNA damage, nucleotide excision repair-deficient chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*SB (slow acetylator) alleles to create a sensitive cell system for measuring DNA adduct formation and mutagenesis. Mutagenesis was concentration-dependent only in the rapid acetylator cell line following treatment with MeIQx, IQ, ABP, and AF. For all carcinogens, induced hypoxanthine phosphoribosyl transferase (hprt) mutant cDNAs were sequenced and over 80% of the single-base substitutions were at G:C base pairs. Arylamine induced-DNA adducts, identified and quantified by liquid chromatography-mass spectrometry, were significantly greater in the rapid than the slow acetylator cell line following treatment with PhIP, McIQx, IQ, AF, and ABP. Following administration of ABP, McIQx, or PhIP, DNA adducts were identified and quantified in tissues from congenic rapid and slow acetylator rats differing only at the NAT2 locus. In isolated mammary epithelial cells, rapid acetylator congenic rats had significantly higher N-acetyltransferase activity than slow acetylators. Higher DNA adduct levels were found in the bladder of slow versus rapid acetylator congenic rats administered ABP whereas higher DNA adduct levels were found in liver of rapid versus slow acetylator congenic rats administered MeIQx, consistent with a role for NAT2 polymorphism in ABP-induced bladder cancer and MeIQx-induced liver cancer. Overall, the findings of this dissertation clearly implicate a role for NAT2 polymorphism in aromatic and heterocyclic amine mutagenesis and DNA adduct formation.

ISBN: 9780549052906Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens.
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245 1 0 $a Role of N-acetyltransferase 2 polymorphism in DNA adduct formation and mutagenesis by aromatic and heterocyclic amine carcinogens.
300 $a 154 p.
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500 $a Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2983.
502 $a Thesis (Ph.D.)--University of Louisville, 2007.
520 $a The interaction between genes and environment may predict cancer risk, and therefore polymorphisms in N-acetyltransferase 2 (NAT2), an important enzyme in xenobiotic metabolism, may play an important role in cancer susceptibility. Humans are exposed to heterocyclic amine carcinogens such as 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx) 2-amino-3-methylimidazo [4,5-f] quinoline (IQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), as well as aromatic amines, such as 4-aminobiphenyl (ABP) and 2-aminofluorene (AF). Bioactivation includes N-hydroxylation catalyzed by CYP1A2 followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). To better understand the role of NAT2 genetic polymorphism in aromatic and heterocyclic amine-induced mutagenesis and DNA damage, nucleotide excision repair-deficient chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*SB (slow acetylator) alleles to create a sensitive cell system for measuring DNA adduct formation and mutagenesis. Mutagenesis was concentration-dependent only in the rapid acetylator cell line following treatment with MeIQx, IQ, ABP, and AF. For all carcinogens, induced hypoxanthine phosphoribosyl transferase (hprt) mutant cDNAs were sequenced and over 80% of the single-base substitutions were at G:C base pairs. Arylamine induced-DNA adducts, identified and quantified by liquid chromatography-mass spectrometry, were significantly greater in the rapid than the slow acetylator cell line following treatment with PhIP, McIQx, IQ, AF, and ABP. Following administration of ABP, McIQx, or PhIP, DNA adducts were identified and quantified in tissues from congenic rapid and slow acetylator rats differing only at the NAT2 locus. In isolated mammary epithelial cells, rapid acetylator congenic rats had significantly higher N-acetyltransferase activity than slow acetylators. Higher DNA adduct levels were found in the bladder of slow versus rapid acetylator congenic rats administered ABP whereas higher DNA adduct levels were found in liver of rapid versus slow acetylator congenic rats administered MeIQx, consistent with a role for NAT2 polymorphism in ABP-induced bladder cancer and MeIQx-induced liver cancer. Overall, the findings of this dissertation clearly implicate a role for NAT2 polymorphism in aromatic and heterocyclic amine mutagenesis and DNA adduct formation.
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