Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

Stevenson, Bradley, Bibby, Jaclyn, Pignatelli, Patricia, Muangnoicharoen, Sant, O’Neill, Paul M., Lian, Lu-Yun, Muller, Pie, Nikou, Dimitra, Steven, Andrew, Hemingway, Janet ORCID: https://orcid.org/0000-0002-3200-7173, Sutcliffe, Michael J. and Paine, Mark ORCID: https://orcid.org/0000-0003-2061-7713 (2011) 'Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed'. Insect Biochemistry and Molecular Biology, Vol 41, Issue 7, pp. 492-502.

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Abstract

Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is a major threat to malaria control programmes. Cytochome P450-mediated detoxification is an important resistance mechanism. CYP6M2 is over-expressed in wild populations of permethrin resistant A. gambiae but its role in detoxification is not clear. CYP6M2 was expressed in Escherichia coli and a structural model was produced to examine its role in pyrethroid metabolism. Both permethrin and deltamethrin were metabolized. Rates were enhanced by A. gambiae cytochrome b(5) with kinetic parameters of K(M)=11±1μM and k(cat)=6.1±0.4 per min for permethrin (1:1 cis-trans) and K(M)=2.0±0.3μM and k(cat)=1.2±0.1 per min for deltamethrin. Mass spectrometry and NMR analysis identified 4'-hydroxy deltamethrin and hydroxymethyl deltamethrin as major and minor deltamethrin metabolites respectively. Secondary breakdown products included cyano(3-hydroxyphenyl)methyl deltamethrate and deltamethric acid. CYP6M2 was most highly transcribed in the midgut and Malpighian tubules of adult A. gambiae, consistent with a role in detoxification. Our data indicates that CYP6M2 plays an important role in metabolic resistance to pyrethroids and thus an important target for the design of new tools to combat malaria.

Item Type:	Article
Additional Information:	Special issue on Toxicology and Resistance.
Subjects:	QX Parasitology > Insects. Other Parasites > QX 515 Anopheles QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
Digital Object Identifer (DOI):	https://doi.org/10.1016/j.ibmb.2011.02.003
Depositing User:	Users 183 not found.
Date Deposited:	25 Aug 2011 08:47
Last Modified:	20 Nov 2024 15:07
URI:	https://archive.lstmed.ac.uk/id/eprint/1801

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