title: Oxidized linoleic acid metabolite-cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain.
abstract: Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.
authors.affiliation: Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ruparel
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Hargreaves
authors.forename: Michael
authors.initials: M
authors.lastname: Eskander
authors.forename: Spencer
authors.initials: S
authors.lastname: Rowan
authors.forename: Jose F A
authors.initials: JFA
authors.lastname: de Almeida
authors.forename: Linda
authors.initials: L
authors.lastname: Roman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henry
mesh_terms: D000818:Animals; D001706:Biopsy; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003782:Dental Pulp / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D019787:Linoleic Acid / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D010084:Oxidation-Reduction; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D051381:Rats; D011984:Sensory Receptor Cells / Q000502:physiology; D050916:TRPV Cation Channels / Q000819:agonists; D014098:Toothache
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D003577:Cytochrome P-450 Enzyme System; D019787:Linoleic Acid; D007654:Ketoconazole
keywords: Cytochrome P450; Dental pulp; OLAM; Peripheral pain; TRPV1