Activation of cytochrome P450IA1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in wild-type and high-activity variant mouse hepatoma cells.

We analyzed the function of a DNA domain located upstream of the cytochrome P450IA1 gene in wild-type (Hepa 1c1c7) mouse hepatoma cells and in high-activity variant (HAV) cells that overtranscribe the gene in response to the inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Transfection experiments indicated that both wild-type and HAV DNA confer responsiveness to TCDD upon the bacterial chloramphenicol acetyltransferase (CAT) gene. However, the level of CAT activity was four- to fivefold higher when the hybrid genes were expressed in the HAV cells. These findings imply that an alteration in a trans-acting function confers the HAV phenotype. Studies of mRNA accumulation imply that TCDD acts by enhancing the rate of mRNA initiation rather than by removing a block in mRNA elongation. We found that both wild-type and HAV cells used the same transcriptional promoter as that described previously for the cytochrome P450IA1 gene in C57BL/6 mouse liver. Both cell types exhibited superinduction of cytochrome P450IA1 gene expression in response to TCDD plus cycloheximide.