Involvement of transcription factor HNF3 gamma in the effect of o-aminoazotoluene on glucocorticoid induction of tyrosine aminotransferase in mice sensitive to its hepatocarcinogenic action

in the rodent liver, hepatocarcinogens inhibit the glucocorticoid induction of several liver-specific genes, including tyrosine aminotransferase (TAT) . A distinct positive correlation exists in mice between the extent of inhi bition of TAT induction after acute administration of o-aminoazotoluene (OA T) and the frequency of liver tumors after chronic exposure to the carcinog en. To elucidate the mechanism of the carcinogenic action, the effects of O AT on the DNA-binding activity of several transcription factors participati ng in the glucocorticoid regulation of TAT gene expression were studied. Th e experimental inbred male mice were sensitive (A/He and SWR/J, tumor induc tion frequency of 75-100%, TAT induction inhibition of 35-50%) and resistan t (CC57BR/Mv and AKR/J, 0-6% and 10-15%, respectively) to OAT. Gel retardat ion experiments showed that hepatocyte nuclear factor 3 (HNF3)gamma DNA-bin ding activity was strongly reduced in nuclear extracts from the livers of O AT-treated A/He and SWR/J mice but only slightly reduced in CC57Br/Mv and A KR/J mice. The DNA-binding activities of Ets, AP1 family members, and GME b inding proteins were unaffected. HNF3 gamma DNA-binding activity was reduce d by 1 h after OAT administration and remained tow for 1 mo, as did inhibit ion of TAT induction in the liver. These results suggested that the inhibit ory effect of OAT on the glucocorticoid induction of TAT is mediated by red uced HNF3 gamma DNA-binding activity. (C) 2001 Wiley-Liss. Inc.