Purpose: In some pheochromocytomas, the tumors contain and secrete greater amounts of adrenaline than do normal adrenal medullas. It is not yet known how adrenaline synthesis is enhanced in the adrenaline-secreting pheochromocytomas.
Materials and methods: As a first step toward understanding the molecular mechanisms by which adrenaline synthesis is controlled in these tumors, we measured the level of mRNA coding for the adrenaline-synthesizing enzyme phenylethanolamine N-methyl transferase (PNMT) and the content of adrenaline in the pheochromocytomas (n = 9), including 3 cases of the adrenaline-secreting type (one of the patients had bilateral pheochromocytomas), and in normal adrenal medullas (n = 7). We then measured the concentration of cortisol, which is thought to regulate the PNMT activity. Finally, we examined the expression of the mRNA for Egr-1, which was recently reported to be a transcriptional factor regulating PNMT gene expression.
Results: In the 4 tissue specimens from 3 adrenaline-secreting pheochromocytomas, the contents of adrenaline and the PNMT mRNA expression were considerably greater than those of the normal adrenal medullas. PNMT immunoreactivity was only detected in the adrenaline-secreting tumors. Three of the 4 specimens showed high concentrations of cortisol. To show the capacity for cortisol production locally in the pheochromocytoma tissues, we showed the expression of a glucocorticoid biosynthetic enzyme, 17alpha-hydroxylase, in the tumors by Western blotting. PNMT expression was found to be associated with 17alpha-hydroxylase expression in the tumors. The glucocorticoid receptor expression was also correlated with PNMT expression in the tumors and the expression of Egr-1 was also high in 3 of the 4 specimens.
Conclusions: These findings indicate that adrenaline production in adrenaline-secreting pheochromocytomas is primarily controlled by the level of PNMT gene expression, and that the gene expression may be enhanced by both cortisol and Egr-1.