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

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)gamma 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. HNF3gamma 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 HNF3gamma DNA-binding activity.

FOXA transcription factors determine the amplitude of glucocorticoid induction of tyrosine aminotransferase in mice

“…A relationship between glucocorticoid induction of TAT and DNA-binding activity of FOXA was revealed after administration of OAT to mice sensitive and resistant to the hepatocarcinogenic effect of this compound. OAT significantly decreased glucocorticoid induction of TAT and DNAbinding activity of FOXA in the liver of sensitive mice (A and SWR), but not in resistant animals (CC57BR and AKR) [4]. These data suggest that FOXA proteins determine the amplitude of glucocorticoid induction of TAT in mice (similarly to rats [8]).…”

“…As differentiated from 3'-MeDAB, specific hepatocarcinogen OAT decreased DNA-binding activity of FOXA and glucocorticoid induction of TAT in SWR mice. Activity of other transcription factors involved in glucocorticoid induction of rat TAT gene (e.g., C/EBP and GME-binding proteins [2,7]) remained unchanged after administration of aminoazo dyes to mice or rats [4,6]. …”

OAT and 3’MeDAB Azo Compounds Similarly Cause Liver Tumors in GR Mice, but Differently Modify Activities of FoxA Transcription Factors

“…For example, 2'3-dimethyl-4-aminoazobenzene (oaminotoluene; OAT; CAS: 97-56-3) reduces DNAbinding activity of FoxA and attenuates glucocorticoid induction of TAT in sensitive mice more than 2-fold. Another azo compound, 3'-methyl-4-dimethylaminoazobenzene (3'MeDAB; CAS: 55-80-1), causes tumors in rats but not in adult mice [6,7]. This compound 2-fold reduces FoxA activity and level of glucocorticoid induction of TAT in rats, but does not change it in mice [6,7].…”

“…Their products regulate cell differentiation and metabolism and maintain cell phenotype [3,5,8,9]. We studied the involvement of FoxA factors in tumor induction on the model of various hepatocarcinogenic substances, primarily azo compounds [6,7,11] characterized by pronounced tissue, species, and strain specifi city. It was found that the decrease in activities of FoxA proteins and attenuation of glucocorticoid induction of tyrosine aminotransferase (L-tyrosine:2-oxoglutarate aminotransferase; TAT) gene expressed exclusively in the liver take place only if the substance is hepatocarcinogenic for this rodent species, strain, or gender, but not in resistant animals.…”

Liver nuclear hormone receptor PPAR, LXR and RXR expression and blood lipid and glucose levels in susceptible and resistent to hepatocarcinogenesis strain of mice

“…В предыдущих работах было показано, что под действием ОАТ происходит нарушение глюкокортикоидной регуляции специфического для печени фермента тирозинаминотрансферазы [10] и ДНК-связывающей активности транскрипционного фактора HNF3 [11] только у линий мышей, предрасположенных к его гепатоканцерогенному действию. Настоящее исследование выявило снижение экспрессии PPAR-a, PPAR-g, RXR-a и RXR-b в печени мышей линии DD, чувствительной к химическому гепатоканцерогенезу, которое могло быть следствием пониженной у них функции гипоталамо-гипофизарной системы.…”