NAT1 Alleles

Historically, NAT1 was thought to be genetically invariant. However, wide interindividual variability in NAT1 activities was suggestive of a genetic polymorphism. The first reported allelic variation at the NAT1 locus was in 1993[7] and marked the beginning of a systematic survey of NAT1 genotypes. To date, 26 different NAT1 alleles have been detected in human populations.[3] However, only a small number of these alter phenotype.

A genotype/phenotype relationship involving the slow acetylator alleles NAT1*14, NAT1*15, NAT1*17, and NAT1*22 in human blood cells exists. Individuals heterozygous for these alleles have approximately half the activity of individuals who are wild-type (NAT1*4). Similar to NAT2 in the liver, low activity was caused by a parallel decrease in NAT1 protein content.[8] A gene-dosage effect similar to that seen for NAT2 alleles also exists for the low activity NAT1 alleles. The NAT1*10 allele has been associated with increased activity in bladder and colon tissue, compared to wild-type.[9] In addition, higher levels of DNA adducts have been detected in bladder tissue from NAT1*10 heterozygotes. The functional significance of this allele is controversial, as several recent studies do not support the idea that NAT1*10 is associated with elevated NAT1 activity.[10-14]

Molecular mechanisms of altered NAT1 acetylation

The molecular mechanism for slow acetylation caused by the NAT1*14, NAT1*15, NAT1*17, and NAT1*22 alleles has been recently elucidated. These alleles produce mutant proteins that are rapidly polyubiquitinated and targeted for degradation by the 26S proteasome. Moreover, degradation correlates with the nonacetylated state of the mutant proteins.[8] It is likely that this same mechanism exists for the slow NAT2 acetylator pheno-type. NAT1*10 contains nucleotide substitutions located in the 3'-untranslated region that alter the consensus polyadenylation signal (AATAAA ! AAAAAA), leading to the suggestion that increased activity may be due to enhanced mRNA stability.

NAT1 allele frequency

The frequency of slow acetylator alleles for NAT1 is low. The most common low activity allele, NAT1*14, has been identified in Caucasian populations ranging from 1.3% to 3.7%. Interestingly, a much higher frequency of the NAT1*14 allele (25%) was reported for a Lebanese population. This indicates that NAT1, like NAT2, shows considerable interethnic variability.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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