Document Detail

Up-regulation of the lysyl hydroxylase 2 gene by acetaminophen and isoniazid is modulated by transcription factor c-Myb.
MedLine Citation:
PMID:  20604837     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: Lysyl hydroxylase 2 (LH2), an isoform of hydroxylase, catalyses the hydroxylation of lysine residues in the telopeptide of collagen to form stable and irreversible cross-linkages in collagen. Increased activity of this enzyme in activated stellate cells in human liver has been proposed to relate to the promotion of hepatic fibrosis. In the present study, we examined the regulation of LH2 expression in drug-induced liver injury in order to clarify the mechanisms behind the hepatic fibrosis caused by certain drugs.
METHODS: The mRNA and protein expression of the target gene were detected by real-time reverse transcription-polymerase chain reaction (RT-PCR) with specific primers and Western blotting with a specific antibody, respectively.
KEY FINDINGS: The expression of LH2 was increased in HepG2 cells incubated with acetaminophen and isoniazid. This increase was accompanied by an increase in the expression of c-myeloblastosis viral oncogene homolog (Myb) mRNA. Over-expression of c-Myb in cells transfected with a c-Myb expression plasmid, pMbm I, caused an increase in the expression of LH2 mRNA. Mutation of the Myb-binding site in the promoter region of the LH2 gene resulted in a loss of transcriptional activation in the reporter gene assay.
CONCLUSIONS: These results suggest that c-Myb modulates the expression of the LH2 gene in HepG2 cells incubated with drugs causing hepatic fibrosis.
Masafumi Kubota; Aya Shinoda; Kazuhiro Iguchi; Yukari Takahashi; Shigeyuki Usui; Tadashi Kiho; Kazuyuki Hirano
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  62     ISSN:  2042-7158     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-07-07     Completed Date:  2011-01-14     Revised Date:  2011-09-13    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  477-84     Citation Subset:  IM    
Department of Medical Pharmaceutics, Gifu Pharmaceutical University, Japan.
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MeSH Terms
Acetaminophen / adverse effects*
Binding Sites
Blotting, Western
Drug-Induced Liver Injury / genetics*,  metabolism
Fibrosis / metabolism
Gene Expression Regulation, Enzymologic*
Genes, Reporter
Hep G2 Cells
Isoniazid / adverse effects*
Liver / metabolism,  pathology
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics*,  metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myb / metabolism*
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcriptional Activation / drug effects*
Reg. No./Substance:
0/Proto-Oncogene Proteins c-myb; 0/RNA, Messenger; 103-90-2/Acetaminophen; 54-85-3/Isoniazid; EC protein, human; EC, 2-Oxoglutarate 5-Dioxygenase

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