We investigated the effect of the
steroid hormone dehydroepiandrosterone (
DHEA) on the hepatic expression and activity of
carcinogen-activating
enzymes, the
cytochromes P450 (
CYP) 1A1, 1A2 and 1B1, in Sprague-Dawley rats. In animals fed
DHEA at 200 or 400 mg/kg
body weight every other day for 2 weeks prior to exposure to the aryl
hydrocarbon dimethylbenz[a]
anthracene (DMBA, 5 mg/kg), there was a dose-dependent decrease in hepatic CYP activity, as measured by
ethoxyresorufin-O (
EROD) assay, from 37.1 to 22.9 and 14.7 pmoles/min/10 microg microsomes, respectively.
DHEA did not directly inhibit microsomal
EROD activity, however, leading us to investigate its effects on
enzyme expression. To test this, we examined
protein and
mRNA levels of the
enzymes. Western blot for
CYP1A1 and
CYP1A2 showed that
DHEA inhibited the increase in hepatic
CYP1A1 and
CYP1A2 enzyme levels that are normally induced by DMBA. DMBA-induced increase in expression of
CYP1A1,
CYP1A2 and CYP1B1
mRNA was similarly blunted in
DHEA-treated animals.
DHEA was also able to significantly reduce the basal expression of
CYP1A1 and
CYP1A2 but not of CYP1B1. These results indicate that
DHEA regulates the expression and, hence, the activity of hepatic
carcinogen-activating
enzymes in vivo, and this may be an important mechanism of its chemopreventive activity.