Inhibition of carcinogen-activating enzymes by 16alpha-fluoro-5-androsten-17-one.
In the present study, we examined the effect of a synthetic analogue of the chemopreventive hormone dehydroepiandrosterone, 16alpha-fluoro-5-androsten-17-one, also known as fluasterone, on the activity and expression of carcinogen-activating enzymes in MCF-7 cells. The increase in cytochrome P450 (CYP) 1A1 and 1B1 activity, as measured by ethoxyresorufin-O-deethylase activity, in cells treated with the carcinogens dimethylbenzanthracene (DMBA) or 2,3,5,7-tetrachlorodibenzo-p-dioxin (TCDD), was inhibited by cotreatment with fluasterone. However, treatment of the cells with fluasterone after induction with DMBA or TCDD failed to decrease enzyme activity, indicating that inhibition was not the result of direct enzyme inhibition. Therefore, we examined the effect of fluasterone on gene expression at the mRNA level. Both DMBA and TCDD caused a dramatic increase in the amount of CYP1A1 and CYP1B1 mRNA, the two major isoforms involved in carcinogen activation in these cells. In cells cotreated with fluasterone, however, there was a dose-dependent decrease in CYP1A1 and CYP1B1 mRNA. Fluasterone also inhibited the basal level of CYP1A1 mRNA but not CYP1B1. Fluasterone inhibited the rate of CYP1A1 promoter-controlled transcription, indicating that it affects the transcriptional regulation of the gene. Actinomycin D chase experiments showed that fluasterone also caused an increase in the degradation of CYP1A1 mRNA, while leaving CYP1B1 mRNA unaffected. These results indicate that fluasterone inhibits the increase in the expression of CYP1A1 normally caused by exposure to carcinogens by both transcriptional and post-transcriptional mechanisms and that CYP1B1 expression is not susceptible to the same post-transcriptional mechanism.
Ciolino
Henry P
HP
Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland 21702-1201, USA. hciolino@ncifcrf.gov
MacDonald
Christopher J
CJ
Yeh
Grace Chao
GC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000493:pharmacokinetics / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C106219:5-androstene-16-fluoro-17-one