@article {De Leon1354, author = {J H De Leon and K J Martell and K P Vatsis and W W Weber}, title = {Slow acetylation in mice is caused by a labile and catalytically impaired mutant N-acetyltransferase (NAT2 9).}, volume = {23}, number = {12}, pages = {1354--1361}, year = {1995}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Three N-acetyltransferase genes (NAT*) were detected in inbred parental and congenic mice. Direct sequencing of NAT2* and liver cytosolic N-acetylation activity determinations with NAT2-specific (p-aminobenzoic acid) and NAT2-selective (2-aminofluorene) substrates have established that the acetylator congenic A.B6 and B6.A mice are genotypically and phenotypically identical to the parental B6 ("wild-type"; rapid acetylator) and A (mutant; slow acetylator) mice, respectively, from which they originated. The apparent KM for p-aminobenzoic acid and thermal inactivation rates determined with liver cytosol from the mutant (A and B6.A) mice were 3-fold and one order of magnitude higher than the corresponding values with liver cytosol from the wild-type (B6 and A.B6) strains. Northern blotting and immunoblotting revealed hepatic NAT2 mRNA and protein bands of equal size and intensity, regardless of the NAT2* genotype or phenotype of the animals. Incubation of liver cytosol from mutant A and B6.A mice at 37 degrees C for 6 hr resulted in virtual cessation of p-aminobenzoate N-acetylation activity, whereas the steady-state level of immunoreactive NAT2 remained unchanged. The results indicate that the amino acid change (N99I) in mutant NAT2* from slow acetylator mice does not hinder the synthesis of hepatic NAT2 protein, but, rather, leads to production of a conformationally modified NAT2 molecule that resists degradation by tissue proteases but is labile and catalytically impaired.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/23/12/1354}, eprint = {https://dmd.aspetjournals.org/content/23/12/1354.full.pdf}, journal = {Drug Metabolism and Disposition} }