Metabolism of Pyrethroids by Mosquito Cytochrome P450 Enzymes: Impact on Vector Control

Abstract

Cytochrome P450 enzymes (P450s) are heme-containing monooxygenases that catalyze metabolisms of various endogenous and exogenous compounds. These P450s constitute a superfamily of enzymes present in various organisms including mammals, plants, bacteria, and insects. P450 enzymes are diverse and metabolize a wide variety of substrates, but their structures are largely conserved. A universal nomenclature has been assigned to P450 superfamily based on their amino acid sequence homology (Nelson et al., 1996). In eukaryotes, P450 is membrane-bound and in general functions to insert one molecule of oxygen into its substrate, with its heme prosthetic group playing a role in substrate oxidation. This catalytic reaction requires a pair of electrons shuttled from NADPH via the NADPH-cytochrome P450 reductase (CYPOR) enzyme, a P450 redox partner, to target P450s (Ortiz de Montellano, 2005). In contrast in bacteria and mitochondria, ferredoxin reductase and iron-sulfur ferredoxin proteins act as a bridge to transfer reducing equivalent from NAD(P)H to target P450s. In insects, P450s are membrane-bound enzymes that play key roles in endogenous metabolisms (i.e. metabolisms of steroid molting and juvenile hormones, and pheromones) and xenobiotic metabolisms, as well as detoxification of insecticides (Feyereisen, 1999). It becomes evident that P450s are implicated in pyrethroid resistance in insects. Insecticides form a mainstay for vector control programs of vector-borne diseases. However intensive uses of insecticides have led to development of insecticide resistance in many insects thus compromising success of insect vector control. In particular pyrethroid resistance has been found widespread in many insects such as house flies, cockroaches, and mosquitoes (Acevedo et al., 2009; Awolola et al., 2002; Cochran, 1989; Hargreaves et al., 2000; Jirakanjanakit et al., 2007). Two major mechanisms have been recorded responsible for insecticide resistance, which are alteration of target sites and metabolic resistance (Hemingway et al., 2004). Metabolic resistance is conferred by increased activities of detoxification enzymes such as P450s, non-specific esterases (Hemingway et al., 2004; Price, 1991). Initial approaches to detect involvement of detoxification mechanisms in metabolic resistance are to compare activities of detoxification enzymes between resistant and