[Biochemical, molecular genetic and ecogenetic studies of polymorphic arylamine N-acetyltransferase (NAT2) in the brain].
Polymorphic arylamine N-acetyltransferase (NAT2) is a detoxification enzyme in the liver. The activity of this enzyme differs for each individual. The difference of this enzyme activity is determined by the polymorphism of this enzyme which is known as N-acetylation polymorphism, and is a representative pharmacogenetic trait. The expression of NAT2 is also seen in brain tissue. However, its role has yet to be elucidated. To clarify the role of NAT2 in the brain, I prepared recombinant NAT2 and examined whether or not L-kynurenine could be an endogenous substrate of NAT2. The spectrophotometric and high performance liquid chromatography analyses of the product of the acetylation reaction using the recombinant enzyme revealed that no N-acetylkynurenine was produced by NAT2 from L-kynurenine. The topographical expression of NAT2 in the brain was examined by the in situ hybridization technique. Hybridization was done using seven digoxigenin-labeled oligonucleotide probes on fresh frozen sections and on paraffin embedded sections of adult rat brain tissue. Though strong signals were observed on the nerve cells and ependym cells, no signals were detected on the glial cells and blood vessels. This finding suggests that the nerve cell-specific endogenous substrate of NAT2 thus exists in the brain, and that the exogenous arylamines are metabolized in ependym. Furthermore, the ecogenetic association of NAT2 and Alzheimer disease (AD) was assessed using the polymerase chain reaction-based restriction fragment length polymorphism technique for NAT2 genotyping. These results revealed the frequency of rapid acetylator phenotype to increase in the non-apoE epsilon 4 carriers of late-onset AD (The odds ratio was 3.0, the 95% confidence interval was 1.3-7.3). This finding suggests that NAT2 polymorphism is one of the risk modifying factor for late-onset AD in non-apoE epsilon 4 carriers.
Ogawa
M
M
Department of Clinical Genetics, Kyushu University, Beppu, Japan.
D000107:Acetylation; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000502:physiology; D001921:Brain / Q000201:enzymology*; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D011110:Polymorphism, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D007737:Kynurenine; D001191:Arylamine N-Acetyltransferase