An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice

Robert P. Erickson; Charlene A. McQueen; Binh Chau; Vijay Gokhale; Masahi Uchiyama; Atsushi Toyoda; Fumiwo Ejima; Naka Maho; Yoshiyuki Sakaki; Yoichi Gondo

doi:10.1016/j.bbrc.2008.03.085

An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice

Robert P. Erickson, Charlene A. McQueen, Binh Chau, Vijay Gokhale, Masahi Uchiyama, Atsushi Toyoda, Fumiwo Ejima, Naka Maho, Yoshiyuki Sakaki, Yoichi Gondo

BIO5, Institute of

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Genetic variation in human N-acetyltransferases (NAT) has been implicated in susceptibility to aromatic amine and hydrazine carcinogens and therapeutic drugs. There are mouse models for variability of human NAT1; however mice with genetic differences in Nat1 (corresponding to human NAT2), have not been available. N-Ethyl-N-nitrosourea (ENU) mutagenesis was used to create genetic variation in Nat1. Among a number of mutations identified, a base-pair change substituting threonine for isoleucine at position 95 was recovered and studied. Molecular models suggested that this substitution would alter substrate binding. Analysis of hepatic Nat1 activity with the selective substrate isoniazid showed that there was a significant reduction in enzymatic activity in the homozygous mutants compared to the parental strain.

Original language	English (US)
Pages (from-to)	285-288
Number of pages	4
Journal	Biochemical and Biophysical Research Communications
Volume	370
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2008.03.085
State	Published - May 30 2008

Keywords

Catalytic triad
Isoniazid metabolism
N-Acetyltransferase
N-Ethyl-N-nitrosourea mutagenesis

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2008.03.085

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@article{208456c3119e45af85f09e1207b44e18,

title = "An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice",

abstract = "Genetic variation in human N-acetyltransferases (NAT) has been implicated in susceptibility to aromatic amine and hydrazine carcinogens and therapeutic drugs. There are mouse models for variability of human NAT1; however mice with genetic differences in Nat1 (corresponding to human NAT2), have not been available. N-Ethyl-N-nitrosourea (ENU) mutagenesis was used to create genetic variation in Nat1. Among a number of mutations identified, a base-pair change substituting threonine for isoleucine at position 95 was recovered and studied. Molecular models suggested that this substitution would alter substrate binding. Analysis of hepatic Nat1 activity with the selective substrate isoniazid showed that there was a significant reduction in enzymatic activity in the homozygous mutants compared to the parental strain.",

keywords = "Catalytic triad, Isoniazid metabolism, N-Acetyltransferase, N-Ethyl-N-nitrosourea mutagenesis",

author = "Erickson, {Robert P.} and McQueen, {Charlene A.} and Binh Chau and Vijay Gokhale and Masahi Uchiyama and Atsushi Toyoda and Fumiwo Ejima and Naka Maho and Yoshiyuki Sakaki and Yoichi Gondo",

note = "Funding Information: This work was supported by the Holsclaw Family Professorship in Human Genetics and Inherited Disease to RPE and partly by Grant-in-Aids for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (Y.G.). We thank Ms. Jessica McVey for administrative assistance. We also thank the members of Sequence Technology Team, RIKEN Genomic Sciences Center for technical support.",

year = "2008",

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day = "30",

doi = "10.1016/j.bbrc.2008.03.085",

language = "English (US)",

volume = "370",

pages = "285--288",

journal = "Biochemical and Biophysical Research Communications",

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TY - JOUR

T1 - An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice

AU - Erickson, Robert P.

AU - McQueen, Charlene A.

AU - Chau, Binh

AU - Gokhale, Vijay

AU - Uchiyama, Masahi

AU - Toyoda, Atsushi

AU - Ejima, Fumiwo

AU - Maho, Naka

AU - Sakaki, Yoshiyuki

AU - Gondo, Yoichi

N1 - Funding Information: This work was supported by the Holsclaw Family Professorship in Human Genetics and Inherited Disease to RPE and partly by Grant-in-Aids for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (Y.G.). We thank Ms. Jessica McVey for administrative assistance. We also thank the members of Sequence Technology Team, RIKEN Genomic Sciences Center for technical support.

PY - 2008/5/30

Y1 - 2008/5/30

N2 - Genetic variation in human N-acetyltransferases (NAT) has been implicated in susceptibility to aromatic amine and hydrazine carcinogens and therapeutic drugs. There are mouse models for variability of human NAT1; however mice with genetic differences in Nat1 (corresponding to human NAT2), have not been available. N-Ethyl-N-nitrosourea (ENU) mutagenesis was used to create genetic variation in Nat1. Among a number of mutations identified, a base-pair change substituting threonine for isoleucine at position 95 was recovered and studied. Molecular models suggested that this substitution would alter substrate binding. Analysis of hepatic Nat1 activity with the selective substrate isoniazid showed that there was a significant reduction in enzymatic activity in the homozygous mutants compared to the parental strain.

AB - Genetic variation in human N-acetyltransferases (NAT) has been implicated in susceptibility to aromatic amine and hydrazine carcinogens and therapeutic drugs. There are mouse models for variability of human NAT1; however mice with genetic differences in Nat1 (corresponding to human NAT2), have not been available. N-Ethyl-N-nitrosourea (ENU) mutagenesis was used to create genetic variation in Nat1. Among a number of mutations identified, a base-pair change substituting threonine for isoleucine at position 95 was recovered and studied. Molecular models suggested that this substitution would alter substrate binding. Analysis of hepatic Nat1 activity with the selective substrate isoniazid showed that there was a significant reduction in enzymatic activity in the homozygous mutants compared to the parental strain.

KW - Catalytic triad

KW - Isoniazid metabolism

KW - N-Acetyltransferase

KW - N-Ethyl-N-nitrosourea mutagenesis

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An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice

Abstract

Keywords

ASJC Scopus subject areas

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