N-acetyltransferase 2 activity and folate levels

Aims: To determine whether increased N-acetyltransferase (NAT) activity might have a toxic effect during development and an influence on folate levels since previous work has shown that only low levels of exogenous NAT can be achieved in constitutionally transgenic mice (Cao et al. 2005). Main methods: A human NAT1 tet-inducible construct was used that would not be expressed until the inducer was delivered. Human NAT1 cDNA was cloned into pTRE2 and injected into mouse oocytes. Two transgenic lines were crossed to mouse line TgN(rtTahCMV)4Uh containing the CMV promoted ter(on). Measurements of red blood cell folate levels in inbred strains of mice were performed. Key findings: Only low levels of human NAT1 could be achieved in kidney (highly responsive in other studies) whether the inducer, doxycycline, was given by gavage or in drinking water. An inverse correlation of folate levels with Nat2 enzyme activity was found. Significance: Since increasing NAT1 activity decreases folate in at least one tissue, the detrimental effect of expression of human NAT1 in combination with endogenous mouse Nat2 may be a consequence of increased catabolism of folate. (C) 2009 Elsevier Inc. All rights reserved.