Carcinogenesis, Vol. 23, No. 3, 457-462,
March 2002
© 2002 Oxford University Press
CARCINOGENESIS |
Nrf2 transactivator-independent GSTP1-1 expression in `GSTP1-1 positive' single cells inducible in female mouse liver by DEN: a preneoplastic character of possible initiated cells
1 Department of Medical Technology, Hirosaki University, School of Health Science, Hon-Cho 66-1, Hirosaki 036-8564,
2 Institute of Basic Medical Sciences and Center for TARA, University of Tsukuba, Tennoudai, Tsukuba 305,
3 Second Department of Pathology, Hirosaki University, School of Medicine, Hirosaki 036-8562,
4 Second Department of Biochemistry, Hirosaki University, School of Medicine, Hirosaki 036-8562 and
5 Aomori Prefectural Institute of Health and Environment, Higashi-Tsukurimichi 1-1-1, Aomori 030-0913, Japan
Whether single cells immunohistochemically positive for glutathione S-transferase P1-1 (GSTP1-1) induced in the female mouse liver by DEN (Hatayama et al., Carcinogenesis, 14, 537–538, 1993) are precursor initiated cells of preneoplastic foci, is of importance in chemical hepatocarcinogenesis. Nrf2 transactivates a wide variety of ARE (anti-oxidant response element)-mediated enzymes including GSTP1-1. Quantitative examination revealed that the basal expression of hepatic GSTP1-1 was 60% lower in Nrf2 gene knock-out female mice–/– than in wild type females, and that treatment with butyrated hydroxyanisole (BHA) increased by 10-fold GSTP1-1 expression in the liver of wild type female mice but not in knockout female mice–/–. Despite the lack of Nrf2, GSTP1-1-positive single cells were detected in livers of DEN-treated female–/– 3 months after treatment. Subsequent BHA feeding to the positive cell-bearing females for one more week clearly showed that the single cells were detectable with females–/– but not with females+/+,+/– due to the strong induction of GSTP1-1 in the surrounding hepatocytes. The sensitivity to DEN hepatocarcinogenesis was not significantly different among genotypes. These results demonstrate that Nrf2 is regulatory in normal hepatocytes but not in the single cells positive for GSTP1-1 inducible in the female mouse liver by DEN. The transcriptional distinction observed for the DEN-transformants is suggestive of a preneoplastic character of precursor initiated cells.
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