An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice.
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.
Erickson
Robert P
RP
Department of Pediatrics, University of Arizona, 1501 N. Campbell Avenue, P.O. Box 245073, Tucson, AZ 85724, USA. erickson@peds.arizona.edu
McQueen
Charlene A
CA
Chau
Binh
B
Gokhale
Vijay
V
Uchiyama
Masahi
M
Toyoda
Atsushi
A
Ejima
Fumiwo
F
Maho
Naka
N
Sakaki
Yoshiyuki
Y
Gondo
Yoichi
Y
D000477:Alkylating Agents / Q000494:pharmacology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000032:analysis / Q000235:genetics*; D002415:Cats; D006224:Cricetinae; D005038:Ethylnitrosourea / Q000494:pharmacology*; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D011817:Rabbits; D051381:Rats; D013379:Substrate Specificity / Q000235:genetics
D000477:Alkylating Agents; D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D005038:Ethylnitrosourea