Involvement of Transcription Factor HNF3γ in the Effect of o-Aminoazotoluene on Glucocorticoid Induction of Tyrosine Aminotransferase in Mice Sensitive to its Hepatocarcinogenic Action

✍ Scribed by Konstantin Y. Kropachev; Vasily I. Kaledin; Victor F. Kobzev; Sergei Y. Plisov; Zoia B. Levashova; Tatyana I. Merkulova

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 158 KB
• Volume: 31
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.1035

✦ Synopsis

Abstract

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 inhibition of TAT induction after acute administration of o‐aminoazotoluene (OAT) and the frequency of liver tumors after chronic exposure to the carcinogen. To elucidate the mechanism of the carcinogenic action, the effects of OAT on the DNA‐binding activity of several transcription factors participating in the glucocorticoid regulation of TAT gene expression were studied. The experimental inbred male mice were sensitive (A/He and SWR/J, tumor induction frequency of 75–100%, TAT induction inhibition of 35–50%) and resistant (CC57BR/Mv and AKR/J, 0–6% and 10–15%, respectively) to OAT. Gel retardation experiments showed that hepatocyte nuclear factor 3 (HNF3)γ DNA‐binding activity was strongly reduced in nuclear extracts from the livers of OAT‐treated A/He and SWR/J mice but only slightly reduced in CC57Br/Mv and AKR/J mice. The DNA‐binding activities of Ets, AP1 family members, and GME binding proteins were unaffected. HNF3γ DNA‐binding activity was reduced by 1 h after OAT administration and remained low for 1 mo, as did inhibition of TAT induction in the liver. These results suggested that the inhibitory effect of OAT on the glucocorticoid induction of TAT is mediated by reduced HNF3γ DNA‐binding activity. © 2001 Wiley‐Liss, Inc.