Regulation of Cytochrome B5 Expression by MiR-223 in Human Liver: Effects on Cytochrome P450 Activities

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2013 Oct 1

PMID 24078287

Citations 11

Authors

Kei Takahashi

Yuki Oda

Yasuyuki Toyoda

Tatsuki Fukami

Tsuyoshi Yokoi

Miki Nakajima

Affiliations

Soon will be listed here.

Abstract

Purpose: Cytochrome b5 (b5) is a hemoprotein that transfers electrons to several enzymes to fulfill functions in fatty acid desaturation, methemoglobin reduction, steroidogenesis, and drug metabolism. Despite the importance of b5, the regulation of b5 expression in human liver remains largely unknown. We investigated whether microRNA (miRNA) might be involved in the regulation of human b5.

Methods: Twenty-four human liver specimens were used for correlation analysis. In silico analysis and luciferase assay were performed to determine whether the predicted miRNAs functionally target to b5. The miR-223 was overexpressed into HepG2 cells infected with adenovirus expressing human cytochrome P450.

Results: In human livers, the b5 protein levels were not positively correlated with the b5 mRNA levels, and miR-223 levels were inversely correlated with the b5 mRNA levels or the translational efficiencies. The luciferase assay showed that miR-223 functionally binds to the element in the 3′-untranslated region of b5 mRNA. The overexpression of miR-223 significantly reduced the endogenous b5 protein level and the mRNA stability in HepG2 cells. Moreover, the overexpression of miR-223 significantly reduced CYP3A4-catalyzed testosterone 6β-hydroxylation activity and CYP2E1-catalyzed chlorzoxazone 6-hydroxylase activity but not CYP1A2-catalyzed 7-ethoxyresorufin O-deethylase activity.

Conclusions: miR-223 down-regulates b5 expression in the human liver, modulating P450 activities.

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References

Alexiou P, Maragkakis M, Papadopoulos G, Reczko M, Hatzigeorgiou A . Lost in translation: an assessment and perspective for computational microRNA target identification. Bioinformatics. 2009; 25(23):3049-55. DOI: 10.1093/bioinformatics/btp565. View

Omura T, Sato R . THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964; 239:2370-8. View

Hosomi H, Akai S, Minami K, Yoshikawa Y, Fukami T, Nakajima M . An in vitro drug-induced hepatotoxicity screening system using CYP3A4-expressing and gamma-glutamylcysteine synthetase knockdown cells. Toxicol In Vitro. 2009; 24(3):1032-8. DOI: 10.1016/j.tiv.2009.11.020. View

Schenkman J, Jansson I . The many roles of cytochrome b5. Pharmacol Ther. 2003; 97(2):139-52. DOI: 10.1016/s0163-7258(02)00327-3. View

Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T . MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res. 2006; 66(18):9090-8. DOI: 10.1158/0008-5472.CAN-06-1403. View

Laios A, OToole S, Flavin R, Martin C, Kelly L, Ring M . Potential role of miR-9 and miR-223 in recurrent ovarian cancer. Mol Cancer. 2008; 7:35. PMC: 2383925. DOI: 10.1186/1476-4598-7-35. View

Yoshitomi S, Ikemoto K, Takahashi J, Miki H, Namba M, Asahi S . Establishment of the transformants expressing human cytochrome P450 subtypes in HepG2, and their applications on drug metabolism and toxicology. Toxicol In Vitro. 2001; 15(3):245-56. DOI: 10.1016/s0887-2333(01)00011-x. View

Hildebrandt A, Estabrook R . Evidence for the participation of cytochrome b 5 in hepatic microsomal mixed-function oxidation reactions. Arch Biochem Biophys. 1971; 143(1):66-79. DOI: 10.1016/0003-9861(71)90186-x. View

Takesue Y, TAKESUE S . Immunological similarity between NADH-cytochrome b5 reductase of erythrocytes and liver microsomes. Biochim Biophys Acta. 1976; 423(2):293-302. DOI: 10.1016/0005-2728(76)90186-9. View

10.

Dai R, Phillips R, Zhang Y, Khan D, Crasta O, Ahmed S . Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood. 2008; 112(12):4591-7. PMC: 2597130. DOI: 10.1182/blood-2008-04-152488. View

11.

Wong Q, Lung R, Law P, Lai P, Chan K, To K . MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008; 135(1):257-69. DOI: 10.1053/j.gastro.2008.04.003. View

12.

Stamatopoulos B, Meuleman N, Haibe-Kains B, Saussoy P, Van den Neste E, Michaux L . microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood. 2009; 113(21):5237-45. DOI: 10.1182/blood-2008-11-189407. View

13.

Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis M, Nervi C . A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005; 123(5):819-31. DOI: 10.1016/j.cell.2005.09.023. View

14.

Garzon R, Marcucci G, Croce C . Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010; 9(10):775-89. PMC: 3904431. DOI: 10.1038/nrd3179. View

15.

Nelson D, Zeldin D, Hoffman S, Maltais L, Wain H, Nebert D . Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. 2004; 14(1):1-18. DOI: 10.1097/00008571-200401000-00001. View

16.

Friedman R, Farh K, Burge C, Bartel D . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2008; 19(1):92-105. PMC: 2612969. DOI: 10.1101/gr.082701.108. View

17.

Calin G, Sevignani C, Dumitru C, Hyslop T, Noch E, Yendamuri S . Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004; 101(9):2999-3004. PMC: 365734. DOI: 10.1073/pnas.0307323101. View

18.

McLaughlin L, Ronseaux S, Finn R, Henderson C, Wolf C . Deletion of microsomal cytochrome b5 profoundly affects hepatic and extrahepatic drug metabolism. Mol Pharmacol. 2010; 78(2):269-78. DOI: 10.1124/mol.110.064246. View

19.

Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y . An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell. 2007; 129(3):617-31. DOI: 10.1016/j.cell.2007.02.048. View

20.

Livingston D, McLachlan S, La Mar G, Brown W . Myoglobin: cytochrome b5 interactions and the kinetic mechanism of metmyoglobin reductase. J Biol Chem. 1985; 260(29):15699-707. View