1-Nitropyrene stabilizes the mRNA of cytochrome P450 1a1, a carcinogen-metabolizing enzyme, via the Akt pathway.
Cytochrome P450 1a1 (Cyp1a1) is a phase I xenobiotic-metabolizing enzyme, the expression of which is mainly driven by the aryl hydrocarbon receptor (AhR). Cyp1a1 messenger (m)RNA is labile. Our study indicates that 1-nitropyrene (1-NP) highly induced Cyp1a1 protein expression, although its induction of AhR transactivation activity was negligible. The fact that the nuclear receptors, CAR, FXR LXR, or PXR, did not induce Cyp1a1 expression indicates that they do not mediate 1-NP's action. When the AhR transcript was degraded by small hairpin (sh)RNA-AhR, 1-NP-induced Cyp1a1 expression largely decreased. In addition, 1-NP did not induce Cyp1a1 in AhR pathway-deficient mutant cells, which indicates that the AhR is essential for 1-NP's action. When Cyp1a1's turnover was examined, 1-NP was able to stabilize the 1-NP- and benzo[a]pyrene (BaP)-induced Cyp1a1 mRNA, but not protein. 1-NP-induced Cyp1a1 mRNA stabilization was mediated by Akt, but not by p38 MAPK, MEK1/2, or JNK. Among aryl hydrocarbons with four annealed phenyl rings, including pyrene, 1-NP, fluoranthene, 3-nitrofluoranthene, chrysene, and 6-nitrochrysene, only 1-NP was able to stabilize Cyp1a1 mRNA. 1-NP's action was gene specific. In conclusion, stabilizing Cyp1a1 mRNA greatly contributed to 1-NP-induced Cyp1a1 expression, which provides new insight into gene regulation by the AhR ligand and mRNA stabilization.
Chu
Wen-Cheng
WC
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan, ROC.
Hong
Wei-Fu
WF
Huang
Min-Cong
MC
Chen
Fei-Yun
FY
Lin
Shin-Chang
SC
Liao
Pei-Jyuan
PJ
Su
Jyan-Gwo J
JG
D000818:Animals; D001564:Benzo(a)pyrene / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011721:Pyrenes / Q000737:chemistry / Q000633:toxicity*; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism
D009153:Mutagens; D011721:Pyrenes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D051057:Proto-Oncogene Proteins c-akt; C032668:1-nitropyrene