Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo.
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.
Ciolino
Henry
H
Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, National Cancer Institute at Frederick, Frederick, MD, USA. hciolino@ncifcrf.gov
MacDonald
Chistopher
C
Memon
Omar
O
Dankwah
Maame
M
Yeh
Grace Chao
GC
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D065633:Cytochrome P-450 CYP1B1; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008861:Microsomes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000276:Adjuvants, Immunologic; D016588:Anticarcinogenic Agents; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1