Metabolic, molecular genetic and toxicological aspects of the acetylation polymorphism in inbred mice.
Over the past 10 years, much fascinating information has been obtained concerning the biochemistry, genetics, toxicological implications and molecular genetics of the N-acetylation polymorphism in mice. Using C57BL/6J (B6) mice as representative of rapid acetylation and A/J (A) mice as representing slow acetylation, it has been shown that the polymorphism observed in N-acetyltransferase (NAT) activity in liver also occurs in kidney, bladder, blood, and other tissues. The development of congenic acetylator mouse lines derived from B6 and A, have provided the necessary tools to study the role of the acetylation polymorphism, on either the B6 or A genetic background, free of nearly all other genetic differences between these strains. Eliminating genes which modify and complicate the differences due to the acetylator genes make the congenic lines very useful in toxicology studies, particularly those involving carcinogenesis. The molecular genetic basis of the acetylator polymorphism in B6 and A mice involves two Nat genes. Nat-1 encodes a protein termed NAT1 which is identical in rapid and slow acetylator strains. Nat-2, however, differs between rapid and slow strains by a single nucleotide change in the coding region. The corresponding NAT2 proteins differ by a single change at amino acid 99: an hydrophilic asparagine in rapid acetylator NAT2 to an hydrophobic isoleucine in NAT2 from slow acetylators. The mechanistic basis for the differences between rapid and slow acetylation in mice appears to be that NAT2 from the rapid B6 strain is 15-fold more stable at 37 degrees C and is transcribed/translated with a maximal efficiency twice that of the enzyme from slow acetylator A mice. Results discussed in this review indicate that mice provide an excellent system for studying the N-acetyltransferase polymorphism and also are useful for modelling several aspects of the human N-acetyltransferase polymorphism.
Levy
G N
GN
Department of Pharmacology, University of Michigan, Ann Arbor 48109.
Martell
K J
KJ
DeLeon
J H
JH
Weber
W W
WW
D000107:Acetylation; D000588:Amines / Q000633:toxicity; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008815:Mice, Inbred Strains; D008967:Molecular Biology; D009374:Neoplasms, Experimental / Q000139:chemically induced; D011110:Polymorphism, Genetic
D000588:Amines; D001191:Arylamine N-Acetyltransferase