Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth.
Eicosanoids participate in the regulation of cellular proliferation. Thus, we observed that prostaglandin E(2) interaction with membrane receptors is involved in the control of 3T6 fibroblast growth induced by serum. However, our results suggested that another arachidonic acid pathway might be implicated in these events. Our results show that 3T6 fibroblasts synthesized hydroxyeicosatetraenoic acids (HETEs) such as 12-HETE through the cytochrome P-450 (CYP450) pathway. However, 3T6 fibroblasts did not produce leukotriene B(4) (LTB(4)), and lipoxygenase inhibitors and LT antagonists failed to inhibit 3T6 fibroblast growth induced by FBS. In contrast, we observed that CYP450 inhibitors such as SKF-525A, 17-octadecynoic acid, 1-aminobenzotriazole, and 6-(2-propargyloxyphenyl)hexanoic acid reduced 12(S)-HETE levels, 3T6 fibroblast growth, and DNA synthesis induced by FBS. The impairment of DNA synthesis and 3T6 fibroblast growth induced by SKF-525A were reversed by exogenous addition of HETEs. Moreover, we report that 5-HETE, 12(S)-HETE, and 15(S)-HETE are mitogenic on 3T6 fibroblast in the absence of another growth factor, and this effect was dependent on the activation of the phosphatidylinositol-3-kinase pathway. In conclusion, our results show that HETEs, probably produced by CYP450, are involved in the control of 3T6 fibroblast growth.
Nieves
Diana
D
Department of Physiology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Moreno
Juan José
JJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D003470:Culture Media; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt