Loading…

Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole

The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pse...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2005-12, Vol.280 (50), p.41129-41136
Main Authors: Trivedi, Vishal, Chand, Prem, Srivastava, Kumkum, Puri, Sunil K, Maulik, Prakas R, Bandyopadhyay, Uday
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page 41136
container_issue 50
container_start_page 41129
container_title The Journal of biological chemistry
container_volume 280
creator Trivedi, Vishal
Chand, Prem
Srivastava, Kumkum
Puri, Sunil K
Maulik, Prakas R
Bandyopadhyay, Uday
description The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.
doi_str_mv 10.1074/jbc.M501563200
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_17423189</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17423189</sourcerecordid><originalsourceid>FETCH-LOGICAL-p240t-f7b4e027bc36ab4f45d779bdc46cd9522ef1048fb3862efab9b18f768fd5c303</originalsourceid><addsrcrecordid>eNpNkDtPwzAUhS0EoqWwMiJPbCl-Js6IKl4SiA4d2CI_VVdOHeIEAX-BP40LReIu9wzfPefoAnCO0Ryjil1tlJ4_cYR5SQlCB2CKkaAF5fjlEEwRIrioCRcTcJLSBuVhNT4GE8xFSTliU_C1CHHofSs_Y7DQb9de-SHBtW1jZ_v47o1MFkYHl0GmNho_ttDJoH0n-yzl1uQjM2qb4A88-DcL09DblOZw2ccuJmsyNuSIIHsvA2ytXsutT-3OVv-LPwVH2TrZs_2egdXtzWpxXzw-3z0srh-LjjA0FK5SzCJSKU1LqZhj3FRVrYxmpTY1J8Q6jJhwiooya6lqhYWrSuEM1xTRGbj8te36-DraNDStT9qGILc2jqnBFSMUizqDF3twVK01Tbcr2n80f9-j3xobdrw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17423189</pqid></control><display><type>article</type><title>Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole</title><source>Open Access: PubMed Central</source><source>ScienceDirect - Connect here FIRST to enable access</source><creator>Trivedi, Vishal ; Chand, Prem ; Srivastava, Kumkum ; Puri, Sunil K ; Maulik, Prakas R ; Bandyopadhyay, Uday</creator><creatorcontrib>Trivedi, Vishal ; Chand, Prem ; Srivastava, Kumkum ; Puri, Sunil K ; Maulik, Prakas R ; Bandyopadhyay, Uday</creatorcontrib><description>The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M501563200</identifier><identifier>PMID: 15863504</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antigens, Protozoan - chemistry ; Antimalarials - pharmacology ; Catalysis ; Clotrimazole - pharmacology ; Dose-Response Relationship, Drug ; Electron Spin Resonance Spectroscopy ; Enzyme Inhibitors - pharmacology ; Free Radicals ; Glutathione - chemistry ; Growth Inhibitors - pharmacology ; Heme - chemistry ; Heme - metabolism ; Hemeproteins - antagonists &amp; inhibitors ; Hemeproteins - chemistry ; Hydrogen Peroxide - metabolism ; Kinetics ; Lipid Peroxidation ; Mass Spectrometry ; Models, Chemical ; Nitrogen - chemistry ; Oxidative Stress ; Oxygen - chemistry ; Peroxidases - antagonists &amp; inhibitors ; Peroxidases - chemistry ; Plasmodium falciparum ; Plasmodium falciparum - enzymology ; Protein Binding ; Reactive Oxygen Species ; Spectrometry, Fluorescence ; Spectrophotometry ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2005-12, Vol.280 (50), p.41129-41136</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15863504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Trivedi, Vishal</creatorcontrib><creatorcontrib>Chand, Prem</creatorcontrib><creatorcontrib>Srivastava, Kumkum</creatorcontrib><creatorcontrib>Puri, Sunil K</creatorcontrib><creatorcontrib>Maulik, Prakas R</creatorcontrib><creatorcontrib>Bandyopadhyay, Uday</creatorcontrib><title>Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.</description><subject>Animals</subject><subject>Antigens, Protozoan - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Catalysis</subject><subject>Clotrimazole - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electron Spin Resonance Spectroscopy</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Free Radicals</subject><subject>Glutathione - chemistry</subject><subject>Growth Inhibitors - pharmacology</subject><subject>Heme - chemistry</subject><subject>Heme - metabolism</subject><subject>Hemeproteins - antagonists &amp; inhibitors</subject><subject>Hemeproteins - chemistry</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Kinetics</subject><subject>Lipid Peroxidation</subject><subject>Mass Spectrometry</subject><subject>Models, Chemical</subject><subject>Nitrogen - chemistry</subject><subject>Oxidative Stress</subject><subject>Oxygen - chemistry</subject><subject>Peroxidases - antagonists &amp; inhibitors</subject><subject>Peroxidases - chemistry</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Protein Binding</subject><subject>Reactive Oxygen Species</subject><subject>Spectrometry, Fluorescence</subject><subject>Spectrophotometry</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNpNkDtPwzAUhS0EoqWwMiJPbCl-Js6IKl4SiA4d2CI_VVdOHeIEAX-BP40LReIu9wzfPefoAnCO0Ryjil1tlJ4_cYR5SQlCB2CKkaAF5fjlEEwRIrioCRcTcJLSBuVhNT4GE8xFSTliU_C1CHHofSs_Y7DQb9de-SHBtW1jZ_v47o1MFkYHl0GmNho_ttDJoH0n-yzl1uQjM2qb4A88-DcL09DblOZw2ccuJmsyNuSIIHsvA2ytXsutT-3OVv-LPwVH2TrZs_2egdXtzWpxXzw-3z0srh-LjjA0FK5SzCJSKU1LqZhj3FRVrYxmpTY1J8Q6jJhwiooya6lqhYWrSuEM1xTRGbj8te36-DraNDStT9qGILc2jqnBFSMUizqDF3twVK01Tbcr2n80f9-j3xobdrw</recordid><startdate>20051216</startdate><enddate>20051216</enddate><creator>Trivedi, Vishal</creator><creator>Chand, Prem</creator><creator>Srivastava, Kumkum</creator><creator>Puri, Sunil K</creator><creator>Maulik, Prakas R</creator><creator>Bandyopadhyay, Uday</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>C1K</scope><scope>F1W</scope><scope>H95</scope><scope>H97</scope><scope>L.G</scope><scope>M7N</scope></search><sort><creationdate>20051216</creationdate><title>Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole</title><author>Trivedi, Vishal ; Chand, Prem ; Srivastava, Kumkum ; Puri, Sunil K ; Maulik, Prakas R ; Bandyopadhyay, Uday</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p240t-f7b4e027bc36ab4f45d779bdc46cd9522ef1048fb3862efab9b18f768fd5c303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Antigens, Protozoan - chemistry</topic><topic>Antimalarials - pharmacology</topic><topic>Catalysis</topic><topic>Clotrimazole - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electron Spin Resonance Spectroscopy</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Free Radicals</topic><topic>Glutathione - chemistry</topic><topic>Growth Inhibitors - pharmacology</topic><topic>Heme - chemistry</topic><topic>Heme - metabolism</topic><topic>Hemeproteins - antagonists &amp; inhibitors</topic><topic>Hemeproteins - chemistry</topic><topic>Hydrogen Peroxide - metabolism</topic><topic>Kinetics</topic><topic>Lipid Peroxidation</topic><topic>Mass Spectrometry</topic><topic>Models, Chemical</topic><topic>Nitrogen - chemistry</topic><topic>Oxidative Stress</topic><topic>Oxygen - chemistry</topic><topic>Peroxidases - antagonists &amp; inhibitors</topic><topic>Peroxidases - chemistry</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Protein Binding</topic><topic>Reactive Oxygen Species</topic><topic>Spectrometry, Fluorescence</topic><topic>Spectrophotometry</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trivedi, Vishal</creatorcontrib><creatorcontrib>Chand, Prem</creatorcontrib><creatorcontrib>Srivastava, Kumkum</creatorcontrib><creatorcontrib>Puri, Sunil K</creatorcontrib><creatorcontrib>Maulik, Prakas R</creatorcontrib><creatorcontrib>Bandyopadhyay, Uday</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) 1: Biological Sciences &amp; Living Resources</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) 3: Aquatic Pollution &amp; Environmental Quality</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Trivedi, Vishal</au><au>Chand, Prem</au><au>Srivastava, Kumkum</au><au>Puri, Sunil K</au><au>Maulik, Prakas R</au><au>Bandyopadhyay, Uday</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2005-12-16</date><risdate>2005</risdate><volume>280</volume><issue>50</issue><spage>41129</spage><epage>41136</epage><pages>41129-41136</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.</abstract><cop>United States</cop><pmid>15863504</pmid><doi>10.1074/jbc.M501563200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2005-12, Vol.280 (50), p.41129-41136
issn 0021-9258
1083-351X
language eng
recordid cdi_proquest_miscellaneous_17423189
source Open Access: PubMed Central; ScienceDirect - Connect here FIRST to enable access
subjects Animals
Antigens, Protozoan - chemistry
Antimalarials - pharmacology
Catalysis
Clotrimazole - pharmacology
Dose-Response Relationship, Drug
Electron Spin Resonance Spectroscopy
Enzyme Inhibitors - pharmacology
Free Radicals
Glutathione - chemistry
Growth Inhibitors - pharmacology
Heme - chemistry
Heme - metabolism
Hemeproteins - antagonists & inhibitors
Hemeproteins - chemistry
Hydrogen Peroxide - metabolism
Kinetics
Lipid Peroxidation
Mass Spectrometry
Models, Chemical
Nitrogen - chemistry
Oxidative Stress
Oxygen - chemistry
Peroxidases - antagonists & inhibitors
Peroxidases - chemistry
Plasmodium falciparum
Plasmodium falciparum - enzymology
Protein Binding
Reactive Oxygen Species
Spectrometry, Fluorescence
Spectrophotometry
Time Factors
title Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T17%3A56%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clotrimazole%20inhibits%20hemoperoxidase%20of%20Plasmodium%20falciparum%20and%20induces%20oxidative%20stress.%20Proposed%20antimalarial%20mechanism%20of%20clotrimazole&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Trivedi,%20Vishal&rft.date=2005-12-16&rft.volume=280&rft.issue=50&rft.spage=41129&rft.epage=41136&rft.pages=41129-41136&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M501563200&rft_dat=%3Cproquest_pubme%3E17423189%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-p240t-f7b4e027bc36ab4f45d779bdc46cd9522ef1048fb3862efab9b18f768fd5c303%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=17423189&rft_id=info:pmid/15863504&rfr_iscdi=true