1,10-phenanthroline stabilizes mRNA of the carcinogen-metabolizing enzyme, cytochrome P450 1a1.
1,10-phenanthroline (phen), flufenamic acid, and indomethacin are inhibitors of aldo-keto reductases 1C1 (AKR1C1), but only phen decreased the benzo[a]pyrene (BaP)-induced cytochrome P450 1a1 (Cyp1a1) protein level. Therefore the decrease in the BaP-induced Cyp1a1 protein level was not due to inhibition of Akr1c1, but to phen itself. Phen decreased the BaP-induced Cyp1a1 promoter activity and protein expression, and in contrast, it increased Cyp1a1 mRNA, resulting from an increase in mRNA stability. Phen is also known as a transition metal ion-chelator. Along with the phen study, we also found that Zn(2+), Fe(2+) and Cu(2+) increased Cyp1a1 mRNA and protein stability. Our results show that phen stabilized the mRNA of Cyp1a1, although it decreased cell viability. In addition, Zn(2+) and Fe(2+) highly neutralized phen's suppression of Cyp1a1 protein expression, but they only slightly neutralized phen's promotion of mRNA stability and suppression of cell viability, and had no effect on phen's suppression of promoter activity. Phen's effect on Cyp1a1 expression was reversible, which indicates that phen is non-covalently linked to its target. This report elucidates a new role for phen of stabilizing Cyp1a1 mRNA, and provides information for further studies on mRNA stabilization.
Chou
Mou-Tsy
MT
Department of Gynecology, Saint Martin De Porres Hospital, Chiayi 600, Taiwan, ROC.
Chu
Wen-Cheng
WC
Hong
Wei-Fu
WF
Huang
Min-Cong
MC
Liu
Wen-Je
WJ
Lin
Shin-Chang
SC
Huang
See-Chang
SC
Chen
Fei-Yun
FY
Hsiao
Wen-Feng
WF
Liu
Yi-Wen
YW
Wu
Jin-Yi
JY
Su
Jyan-Gwo J
JG
D001564:Benzo(a)pyrene / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007501:Iron / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology
D002413:Cations, Divalent; D010618:Phenanthrolines; D012333:RNA, Messenger; D015262:Xenobiotics; D001564:Benzo(a)pyrene; D003300:Copper; D007501:Iron; D019363:Cytochrome P-450 CYP1A1; D015032:Zinc; C025205:1,10-phenanthroline