1-Nitropyrene Stabilizes the mRNA of Cytochrome P450 1a1, a Carcinogen-Metabolizing Enzyme, via the Akt Pathway

• Published in: Chemical research in toxicology 2009-12, Vol.22 (12), p.1938-1947
• Main Authors: Chu, Wen-Cheng, Hong, Wei-Fu, Huang, Min-Cong, Chen, Fei-Yun, Lin, Shin-Chang, Liao, Pei-Jyuan, Su, Jyan-Gwo J
• Format: Article
• Language: English
• Subjects: Animals; Benzo(a)pyrene - chemistry; Benzo(a)pyrene - pharmacology; Cell Line, Tumor; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Mice; Mutagens - chemistry; Mutagens - toxicity; Proto-Oncogene Proteins c-akt - metabolism; Pyrenes - chemistry; Pyrenes - toxicity; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; RNA Interference; RNA Stability; RNA, Messenger - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx900241g

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.