The cytochrome P450-dependent monooxygenases are an extremely important metabolic system involved in the metabolism of endogenous compounds and xenobiotics. Collectively, P450 monooxygenases can metabolize numerous substrates and carry out multiple oxidative reactions. The large number of substrates metabolized is due to the plethora of P450 isoforms and to the broad substrate specificity of some isoforms. Monooxygenases of insects have several functional roles, including growth, development, feeding and protection against xenobiotics, including resistance to pesticides and tolerance to plant toxins. This review begins with background information about P450s and their evolution, followed by a discussion of the extraordinary diversity of insect P450s. Given the enormous interest in studying individual P450s, we then provide a synopsis of the different methods that have been used in their isolation and the substrates that are known to be metabolized. We conclude by summarizing the lessons we have learned from the study of individual insect P450s, including their roles in insecticide resistance, plant-insect interactions and insect physiology. However, these studies are just the 'tip of the iceberg'. Our knowledge continues to expand at a rapid pace, suggesting that the next decade will outpace the last in terms of improving our understanding of the cytochromes P450 of insects.

One of the challenges faced in malarial control is the acquisition of insecticide resistance that has developed in mosquitoes that are vectors for this disease. Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa, has over the years developed resistance to insecticides including dieldrin, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), and pyrethroids. Previous microarray studies using fragments of 230 An. gambiae genes identified five P450 loci, including CYP4C27, CYP4H15, CYP6Z1, CYP6Z2, and CYP12F1, that showed significantly higher expression in the DDT-resistant ZAN/U strain compared with the DDT-susceptible Kisumu strain. To predict whether either of the CYP6Z1 and CYP6Z2 proteins might potentially metabolize DDT, we generated and compared molecular models of these two proteins with and without DDT docked in their catalytic sites. This comparison indicated that, although these two CYP6Z proteins share high sequence identity, their metabolic profiles were likely to differ dramatically from the larger catalytic site of CYP6Z1, potentially involved in DDT metabolism, and the more constrained catalytic site of CYP6Z2, not likely to metabolize DDT. Heterologous expressions of these proteins have corroborated these predictions: only CYP6Z1 is capable of metabolizing DDT. Overlays of these models indicate that slight differences in the backbone of SRS1 and variations of side chains in SRS2 and SRS4 account for the significant differences in their catalytic site volumes and DDT-metabolic capacities. These data identify CYP6Z1 as one important target for inhibitor design aimed at inactivating insecticide-metabolizing P450s in natural populations of this malarial mosquito.cytochrome P450 monooxygenases ͉ insecticides ͉ plant allelochemicals I n 2004, the World Health Organization reported that up to 2.7 million people die of malaria every year with 80-90% of these deaths occurring in Africa (ref. 1 and www.africanfront.com/ AIDS1.php). Many prevention and treatment strategies have been developed to tackle this life-threatening disease from the side of the mosquito vector and that of the human host (2, 3). These range from antimalarial drugs to indoor spraying of insecticides and use of bed nets treated with pyrethroid insecticides. Although these practices have helped reduce human mortality, various issues have emerged with mosquito vectors developing insecticide resistance and parasites developing drug resistance. Both of these significantly reduce the efficacy of current malarial prevention and treatment practices (2, 4-8).The development of insecticide resistance in mosquito vectors is illustrated by Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa (4, 6). Throughout the years, people have reported Anopheles resistance (albeit low-level resistance) to various insecticides including dieldrin (a cyclodiene-type insecticide), 1,1-bis(pchlorophenyl)-2,2,2-trichloroethane (DDT), and pe...

No abstract

No abstract

No abstract