A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine
Identifieur interne : 001594 ( Main/Exploration ); précédent : 001593; suivant : 001595A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine
Auteurs : Richard K. Haynes [Hong Kong, Italie] ; Kwan-Wing Cheu ; Ka-Yan Li ; Maggie Mei-Ki Tang ; Ho-Ning Wong ; Min-Jiao Chen ; Zu-Feng Guo ; Zhi-Hong Guo ; Paolo Coghi [Italie] ; Diego Monti [Italie]Source :
- ChemMedChem [ 1860-7179 ] ; 2011-09-05.
Abstract
Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH2 of riboflavin (RF), and FADH2 of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH2, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin‐mediated oxidation of RFH2 generated from N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–RF, or FADH2 generated from NADPH or NADPH–Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor–acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ–MB and CQ–artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP–CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ‐resistance transporter (PfCRT).
The parallel in antimalarial mechanism of action of methylene blue (MB) with artemisinins extends to mutual synergism, and antagonism of each by chloroquine (CQ). The latter effect correlates with artemisinin‐mediated inhibition of oxidation of leucomethylene blue (LMB) and reduced flavins, an effect that is reversed by verapamil.
Url:
DOI: 10.1002/cmdc.201100184
Affiliations:
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Venezian 21</wicri:regionArea><wicri:noRegion>Via G. Venezian 21</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">ChemMedChem</title><title level="j" type="alt">CHEMMEDCHEM</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><biblScope unit="vol">6</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1603">1603</biblScope><biblScope unit="page" to="1615">1615</biblScope><biblScope unit="page-count">13</biblScope><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2011-09-05">2011-09-05</date></imprint><idno type="ISSN">1860-7179</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH2 of riboflavin (RF), and FADH2 of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH2, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin‐mediated oxidation of RFH2 generated from N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–RF, or FADH2 generated from NADPH or NADPH–Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor–acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ–MB and CQ–artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP–CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ‐resistance transporter (PfCRT).</div><div type="abstract" xml:lang="en">The parallel in antimalarial mechanism of action of methylene blue (MB) with artemisinins extends to mutual synergism, and antagonism of each by chloroquine (CQ). The latter effect correlates with artemisinin‐mediated inhibition of oxidation of leucomethylene blue (LMB) and reduced flavins, an effect that is reversed by verapamil.</div></front></TEI><affiliations><list><country><li>Hong Kong</li><li>Italie</li></country></list><tree><noCountry><name sortKey="Chen, Min Iao" sort="Chen, Min Iao" uniqKey="Chen M" first="Min-Jiao" last="Chen">Min-Jiao Chen</name><name sortKey="Cheu, Kwan Ing" sort="Cheu, Kwan Ing" uniqKey="Cheu K" first="Kwan-Wing" last="Cheu">Kwan-Wing Cheu</name><name sortKey="Guo, Zhi Ong" sort="Guo, Zhi Ong" uniqKey="Guo Z" first="Zhi-Hong" last="Guo">Zhi-Hong Guo</name><name sortKey="Guo, Zu Eng" sort="Guo, Zu Eng" uniqKey="Guo Z" first="Zu-Feng" last="Guo">Zu-Feng Guo</name><name sortKey="Li, Ka An" sort="Li, Ka An" uniqKey="Li K" first="Ka-Yan" last="Li">Ka-Yan Li</name><name sortKey="Tang, Maggie Mei I" sort="Tang, Maggie Mei I" uniqKey="Tang M" first="Maggie Mei-Ki" last="Tang">Maggie Mei-Ki Tang</name><name sortKey="Wong, Ho Ing" sort="Wong, Ho Ing" uniqKey="Wong H" first="Ho-Ning" last="Wong">Ho-Ning Wong</name></noCountry><country name="Hong Kong"><noRegion><name sortKey="Haynes, Richard K" sort="Haynes, Richard K" uniqKey="Haynes R" first="Richard K." last="Haynes">Richard K. Haynes</name></noRegion></country><country name="Italie"><noRegion><name sortKey="Haynes, Richard K" sort="Haynes, Richard K" uniqKey="Haynes R" first="Richard K." last="Haynes">Richard K. Haynes</name></noRegion><name sortKey="Coghi, Paolo" sort="Coghi, Paolo" uniqKey="Coghi P" first="Paolo" last="Coghi">Paolo Coghi</name><name sortKey="Monti, Diego" sort="Monti, Diego" uniqKey="Monti D" first="Diego" last="Monti">Diego Monti</name><name sortKey="Monti, Diego" sort="Monti, Diego" uniqKey="Monti D" first="Diego" last="Monti">Diego Monti</name><name sortKey="Monti, Diego" sort="Monti, Diego" uniqKey="Monti D" first="Diego" last="Monti">Diego Monti</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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