Change of 7α-hydroxy-dehydroepiandrosterone levels in serum of mice treated by cytochrome P450-modifying agents

Dehydroepiandrosterone (DHEA) is 7 alpha-hydroxylated in liver, brain and other organs of murine and in other species. Several works suggest that the 7 alpha-hydroxy-DHEA produced may be one of the native antiglucocorticoids, and compounds modifying its production may prove useful in investigation of 7 alpha-hydroxy-DHEA production and effects. After treatment of mice with dexamethasone, phenobarbital, trilostane, melatonin or metyrapone,. we have used gas chromatography-mass spectrometry with negative ion detection for measurement of 7 alpha-hydroxy-DHEA levels in serum of control and treated animals. The 7 alpha-hydroxylating rates of liver and brain microsomes from the same animals were also measured. Results showed that serum levels of 7 alpha-hydroxy-DHEA were significantly increased after treatment by all compounds except metyrapone. Significantly increased 7 alpha-hydroxy-DHEA levels were directly related with significantly increased 7 alpha-hydroxylation yields in liver and not in brain. In contrast, metyrapone decreased 7 alpha-hydroxylation in liver and brain. These findings indicate that in brain and in liver, different enzyme systems may be responsible for production of 7 alpha-hydroxy-DHEA and that treatment-induced modifications of circulating 7 alpha-hydroxy-DHEA levels are mainly due to change of 7 alpha-hydroxylating rates in liver.