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

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Abstract
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.