PMID: 1441598Sep 1, 1992Paper

Polymorphisms of N-acetyltransferase genes

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
D M GrantU A Meyer

Abstract

1. A genetic polymorphism of human liver arylamine N-acetyltransferase (NAT) enzyme activity leads to wide variation in the disposition of many drugs and potential carcinogens, resulting in differential susceptibility to chemical-induced toxicity. 2. During studies to determine the biochemical and molecular mechanisms underlying this pharmacogenetic defect, we cloned two human genes, NAT1 and NAT2, which encode the functional acetylating enzymes NAT1 and NAT2. 3. NAT1 and NAT2 are both expressed in human liver cytosol, the latter as two closely related isoforms NAT2A and NAT2B. 4. NAT2 gene locus is the site of the human acetylation polymorphism, because its products NAT2A and NAT2B selectively acetylate 'polymorphic' arylamine substrates (e.g. sulphamethazine), and since the liver content of these isozymes is markedly reduced in genetically slow acetylator subjects. 5. NAT1 shows marked kinetic selectivity for 'monomorphic' substrates (e.g. p-aminobenzoic acid) whose in vivo acetylation rates do not correlate with the acetylation polymorphism. 6. Despite the drastic reduction in NAT2A/B proteins in livers from phenotypically slow acetylators, levels of the NAT2 gene transcript are not altered. 7. Three common mutant alleles at...Continue Reading

References

Sep 1, 1977·Clinical Pharmacology and Therapeutics·D E Drayer, M M Reidenberg
Jun 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·M BlumU A Meyer
Dec 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·M BlumU A Meyer
Jan 1, 1989·Pharmacology & Therapeutics·D A Evans
Apr 1, 1984·British Journal of Clinical Pharmacology·D M GrantW Kalow
Aug 13, 1960·British Medical Journal·D A EvansV A McKUSICK

Citations

Aug 7, 2007·International Archives of Occupational and Environmental Health·Margareta LittorinStaffan Skerfving
Apr 20, 2011·Circulation·Dan M RodenC Michael Stein
Mar 13, 2002·Epilepsia·Dan M Roden
Jun 8, 2002·Pharmacogenomics·P Meisel
Jul 18, 2002·Nature Reviews. Drug Discovery·Dan M Roden, Alfred L George
Feb 26, 2010·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Katy WalkerBabasaheb Sonawane

Related Concepts

Acetylation
Acetyltransferase
Liver
Genetic Polymorphism
Whole Genomic DNA Probes
Nested Polymerase Chain Reaction

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