PT  - JOURNAL ARTICLE
AU  - T. W. Madanayake
AU  - T. P. Fidler
AU  - T. M. Fresquez
AU  - N. Bajaj
AU  - A. M. Rowland
TI  - Cytochrome P450 2S1 Depletion Enhances Cell Proliferation and Migration in Bronchial Epithelial Cells, in Part, through Modulation of Prostaglandin E<sub>2</sub> Synthesis
AID  - 10.1124/dmd.112.046466
DP  - 2012 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 2119--2125
VI  - 40
IP  - 11
4099  - http://dmd.aspetjournals.org/content/40/11/2119.short
4100  - http://dmd.aspetjournals.org/content/40/11/2119.full
SO  - Drug Metab Dispos2012 Nov 01; 40
AB  - 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 G2 (PGG2)] at nanomolar concentrations. Arachidonic acid is converted to prostaglandin precursors [PGG2 and prostaglandin H2 (PGH2)] through COX. These precursors are used to synthesize numerous prostanoids, including PGE2. Prostaglandin E2 (PGE2) promotes cell proliferation and cell migration and inhibits apoptosis. CYP2S1 metabolism of PGG2 presumably sequesters PGG2 and PGH2, making them unavailable for synthesis of prostanoids such as PGE2. 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 PGE2 synthesis, the reduction in CYP2S1 expression doubled intracellular PGE2 levels. Pharmacological administration of PGE2 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.