TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin

Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications—the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mech...

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Veröffentlicht in:Journal of dental research 2017-07, Vol.96 (7), p.832-839
Hauptverfasser: López-González, M.J., Luis, E., Fajardo, O., Meseguer, V., Gers-Barlag, K., Niñerola, S., Viana, F.
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container_end_page 839
container_issue 7
container_start_page 832
container_title Journal of dental research
container_volume 96
creator López-González, M.J.
Luis, E.
Fajardo, O.
Meseguer, V.
Gers-Barlag, K.
Niñerola, S.
Viana, F.
description Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications—the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment.
doi_str_mv 10.1177/0022034517695518
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The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment.</description><identifier>ISSN: 0022-0345</identifier><identifier>EISSN: 1544-0591</identifier><identifier>DOI: 10.1177/0022034517695518</identifier><identifier>PMID: 28571526</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Acetanilides - pharmacology ; Allyl isothiocyanate ; Animals ; Anticonvulsants ; Anticonvulsants - adverse effects ; Antihypertensives ; Antioxidants ; Antioxidants - pharmacology ; Ascorbic acid ; Blotting, Western ; Calcium (intracellular) ; Calcium channels ; Calcium Channels - metabolism ; Calcium permeability ; Capsaicin ; Capsaicin receptors ; Cell Line ; Cell proliferation ; Collagen ; Dentistry ; Experiments ; Extracellular matrix ; Fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Folic acid ; Gingiva ; Gingiva - cytology ; Gingival Overgrowth - chemically induced ; Humans ; Hypotheses ; Intracellular ; Isothiocyanate ; Laboratories ; Molecular modelling ; Nerve Tissue Proteins - metabolism ; Oral hygiene ; Oxidative stress ; Patch-Clamp Techniques ; Penicillin ; Phenytoin ; Phenytoin - adverse effects ; Polymerase chain reaction ; Purines - pharmacology ; Real-Time Polymerase Chain Reaction ; Reverse transcription ; Staining and Labeling ; Transient Receptor Potential Channels - metabolism ; Transient receptor potential proteins ; TRPA1 Cation Channel ; TRPV Cation Channels - metabolism ; Vitamin E ; Vitamins</subject><ispartof>Journal of dental research, 2017-07, Vol.96 (7), p.832-839</ispartof><rights>International &amp; American Associations for Dental Research 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-e730e1884d01a0ff1c47667518574db04621b6017a78ad220f707c4a37c47e863</citedby><cites>FETCH-LOGICAL-c365t-e730e1884d01a0ff1c47667518574db04621b6017a78ad220f707c4a37c47e863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/0022034517695518$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/0022034517695518$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,780,784,21819,27924,27925,43621,43622</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28571526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>López-González, M.J.</creatorcontrib><creatorcontrib>Luis, E.</creatorcontrib><creatorcontrib>Fajardo, O.</creatorcontrib><creatorcontrib>Meseguer, V.</creatorcontrib><creatorcontrib>Gers-Barlag, K.</creatorcontrib><creatorcontrib>Niñerola, S.</creatorcontrib><creatorcontrib>Viana, F.</creatorcontrib><title>TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin</title><title>Journal of dental research</title><addtitle>J Dent Res</addtitle><description>Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications—the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. 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Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>28571526</pmid><doi>10.1177/0022034517695518</doi><tpages>8</tpages></addata></record>
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subjects Acetanilides - pharmacology
Allyl isothiocyanate
Animals
Anticonvulsants
Anticonvulsants - adverse effects
Antihypertensives
Antioxidants
Antioxidants - pharmacology
Ascorbic acid
Blotting, Western
Calcium (intracellular)
Calcium channels
Calcium Channels - metabolism
Calcium permeability
Capsaicin
Capsaicin receptors
Cell Line
Cell proliferation
Collagen
Dentistry
Experiments
Extracellular matrix
Fibroblasts
Fibroblasts - drug effects
Fibroblasts - metabolism
Folic acid
Gingiva
Gingiva - cytology
Gingival Overgrowth - chemically induced
Humans
Hypotheses
Intracellular
Isothiocyanate
Laboratories
Molecular modelling
Nerve Tissue Proteins - metabolism
Oral hygiene
Oxidative stress
Patch-Clamp Techniques
Penicillin
Phenytoin
Phenytoin - adverse effects
Polymerase chain reaction
Purines - pharmacology
Real-Time Polymerase Chain Reaction
Reverse transcription
Staining and Labeling
Transient Receptor Potential Channels - metabolism
Transient receptor potential proteins
TRPA1 Cation Channel
TRPV Cation Channels - metabolism
Vitamin E
Vitamins
title TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin
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