Abstract 4423: Transgenic liver expression of human arylamine N-acetyltransferase NAT2 restores sensitivity of male Nat1/2 null mice to 4-aminobiphenyl-induced liver tumorigenesis

Abstract

Abstract We recently observed that male Nat1/2(-/-) mice, which are deficient in the arylamine N-acetyltransferases Nat1 and Nat2, have a significantly lower incidence and multiplicity of liver tumors than wild-type C57BL/6 mice after their neonatal exposure to the aromatic amine carcinogen 4-aminobiphenyl (ABP). Female mice showed low or no liver tumors from ABP exposure regardless of Nat1/2 status. The goal of the present study was to determine the effect of liver-selective transgenic expression of human NAT2 on ABP-induced liver tumorigenicity in male and female Nat1/2(-/-) mice. We generated a hNAT2tgNat1/2(-/-) strain of mice that express human NAT2 selectively in liver on a Nat1/2 null background, exposed male and female mice to either DMSO vehicle, a low dose (600 nmoles) or a high dose (1200 nmoles) of ABP during the second postnatal week, and assessed mice for tumor growth at one year of age. Male hNAT2tgNat1/2(-/-) mice had liver tumor incidences of 29% (low dose) and 61% (high dose), which more closely resembled those of C57BL/6 mice (60% and 69%, respectively) than those of Nat1/2(-/-) mice (0% and 35%, respectively). This suggests that human NAT2 is capable of substantially restoring the sensitivity of mice to ABP-induced liver tumorigenicity that is lost by the absence of mouse Nat1 and Nat2. On the other hand, female hNAT2tgNat1/2(-/-) mice were still as resistant to liver tumors as C57BL/6 or Nat1/2(-/-) mice. No tumors were observed in any other organs. These results suggest that the human and mouse NAT enzymes play similar roles in enhancing liver tumor growth, and that the mechanism of female protection against ABP-induced tumor growth is unrelated to NAT status. However, neither the sex nor the NAT status of the mice appear to be correlated with the ability of ABP to produce acute DNA-damaging or mutation-inducing effects in liver. This suggests that the role of the human and mouse NAT enzymes in promoting liver tumor growth in mice may be due to a mechanism that is independent of their ability to influence the process of ABP metabolic activation and subsequent DNA damage leading to tumor initiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4423. doi:1538-7445.AM2012-4423