Document Detail


Cytochrome P450 2S1 depletion enhances cell proliferation and migration in bronchial epithelial cells, in part, through modulation of prostaglandin E(2) synthesis.
MedLine Citation:
PMID:  22863683     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytochromes P450 (P450s) contribute to the metabolic activation and inactivation of various endogenous substrates. Despite years of research, the physiological role of CYP2S1 remains unknown. CYP2S1 has demonstrated NADPH P450-reductase-independent metabolism of cyclooxygenase (COX)-derived prostaglandins [e.g., prostaglandin G(2) (PGG(2))] at nanomolar concentrations. Arachidonic acid is converted to prostaglandin precursors [PGG(2) and prostaglandin H(2) (PGH(2))] through COX. These precursors are used to synthesize numerous prostanoids, including PGE(2). Prostaglandin E(2) (PGE(2)) promotes cell proliferation and cell migration and inhibits apoptosis. CYP2S1 metabolism of PGG(2) presumably sequesters PGG(2) and PGH(2), making them unavailable for synthesis of prostanoids such as PGE(2). Whether CYP2S1 contributes to prostaglandin metabolism and influences cell physiological remains to be determined. The purpose of this study was to evaluate the physiological role of CYP2S1, if any, in human bronchial epithelial cells [SV40-derived bronchial epithelial cell line (BEAS-2B)]. To do this, we used small interfering RNA to deplete CYP2S1 mRNA and protein by approximately 75% and evaluated the impact of CYP2S1 depletion on cell proliferation and migration. CYP2S1 depletion enhanced both cell proliferation and migration in BEAS-2B cells. Consistent with the proposed role of CYP2S1 in PGE(2) synthesis, the reduction in CYP2S1 expression doubled intracellular PGE(2) levels. Pharmacological administration of PGE(2) enhanced cell proliferation in BEAS-2B cells but failed to promote migration. Our data reveal an important role for CYP2S1 in the regulation of cell proliferation and migration, occurring in part through modulation of prostaglandin synthesis.
Authors:
T W Madanayake; T P Fidler; T M Fresquez; N Bajaj; A M Rowland
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-03
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  40     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-18     Completed Date:  2013-06-12     Revised Date:  2014-01-13    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2119-25     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Bronchi / metabolism*
Cell Growth Processes / physiology
Cell Line
Cell Movement / physiology*
Cytochrome P-450 Enzyme System / deficiency,  genetics,  metabolism*
Dinoprostone / biosynthesis*,  genetics,  metabolism
Epithelial Cells / cytology,  enzymology,  metabolism
Humans
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Respiratory Mucosa / cytology,  enzymology,  metabolism*
Grant Support
ID/Acronym/Agency:
R25-GM061222/GM/NIGMS NIH HHS; SC2 CA179928/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/RNA, Messenger; 0/RNA, Small Interfering; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/CYP2S1 protein, human; K7Q1JQR04M/Dinoprostone
Comments/Corrections

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