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In vivo and in vitro metabolism of aromatic amines in transgenic mice with liver‐selective expression of human arylamine N‐acetyltransferase NAT2
Author(s) -
Grant Denis Michael,
Sugamori Kim S,
Brenneman Debbie
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.920.8
Subject(s) - in vivo , transgene , genetically modified mouse , microbiology and biotechnology , biology , biochemistry , in vitro , chemistry , gene , genetics
To aid studies into the role of liver‐selective expression of human arylamine N‐acetyltransferase NAT2 in tissue patterns of aromatic amine toxicity, we developed a transgenic mouse line that expresses human NAT2 selectively in liver by linking the human NAT2 protein‐coding exon to the mouse albumin promoter, injecting the transgene into mouse oocytes, and testing offspring for transgene incorporation by Southern blotting. We obtained one transgenic founder that possesses a single copy of the human NAT2 coding region. Transgenic animals and offspring of matings with Nat1/Nat2 null mice were assayed for human NAT2 expression using the human NAT2‐selective substrate sulfamethazine (SMZ) and the NAT1‐selective substrate p ‐aminosalicylate (PAS) in in vitro enzyme assays and in vivo plasma pharmacokinetic studies. SMZ‐NAT activity was present in liver cytosols from transgenic animals at levels comparable to those observed in livers from human NAT2 rapid acetylators, while activity was absent in Nat1/Nat2 null controls. Activity in colon was low and that in other tissues was undetectable. SMZ was more efficiently cleared in vivo by human NAT2 transgenic mice than non‐transgenics, while the clearance of PAS was similar between the strains. These mice will be a valuable tool to investigate the importance of liver NAT2 expression in the metabolism and toxicity of aromatic amines in humans.