A novel role of Drosophila cytochrome P450-4e3 in permethrin insecticide tolerance

Abstract

The exposure of insects to xenobiotics, such as insecticides, triggers a complex defence response necessary for survival. This response includes the induction of genes that encode key Cytochrome P450 monooxygenase detoxification enzymes. Drosophila melanogaster Malpighian (renal) tubules are critical organs in the detoxification and elimination of these foreign compounds, so the tubule response induced by dietary exposure to the insecticide permethrin was examined. We found that expression of the gene encoding Cytochrome P450-4e3 (Cyp4e3) is significantly up-regulated by Drosophila fed on permethrin and that manipulation of Cyp4e3 levels, specifically in the principal cells of the Malpighian tubules, impacts significantly on the survival of permethrin-fed flies. Both dietary exposure to permethrin and Cyp4e3 knockdown cause a significant elevation of oxidative stress-associated markers in the tubules, including H2O2 and lipid peroxidation byproduct, HNE (4-hydroxynonenal). Thus, Cyp4e3 may play an important role in regulating H2O2 levels in the endoplasmic reticulum (ER) where it resides, and its absence triggers a JAK/STAT and NF-κB-mediated stress response, similar to that observed in cells under ER stress. This work increases our understanding of the molecular mechanisms of insecticide detoxification and provides further evidence of the oxidative stress responses induced by permethrin metabolism.

Identification of a novel cytochrome P450 CYP3356A1 linked with insecticide detoxification in Bradysia odoriphaga

“…To better understand the function of CYP3356A1 , distribution of the gene in the tissues of B. odoriphaga was also detected. It has been reported that tissue‐specific expression of detoxification‐related genes might illustrate some functions of their biological and physiological roles . In our results, the highest expression level of CYP3356A1 was observed in the Malpighian tubule, followed by midgut and fat body.…”

“…It has been reported that tissue-specific expression of detoxification-related genes might illustrate some functions of their biological and physiological roles. 47,48 In our results, the highest expression level of CYP3356A1 was observed in the Malpighian tubule, followed by midgut and fat body. Because insect Malpighian tubules play important roles in the detoxification of exogenic compounds such as insecticides, genes encoding detoxification enzymes are typically highly expressed within this organ.…”

Comparative CYP‐omic analysis between the DDT‐susceptible and ‐resistant Drosophila melanogaster strains 91‐C and 91‐R

“…Previous studies have focused on the role of P450s in the detoxification of intracellular and xenobiotic compounds . Several P450s are implicated in the degradation of caffeine, and the up‐regulation of Cyp4e3 in the Malpighian tubules is associated with permethrin resistance and surmised to impact cellular response to stress . To date, the functional role of the Cyp6g1 gene has been particularly focused upon in order to identify the mechanism by which this P450 metabolizes insecticides in D. melanogaster .…”

“…[23][24][25][26] Several P450s are implicated in the degradation of caffeine, 27 and the up-regulation of Cyp4e3 in the Malpighian tubules is associated with permethrin resistance and surmised to impact cellular response to stress. 28 To date, the functional role of the Cyp6g1 gene has been particularly focused upon in order to identify the mechanism by which this P450 metabolizes insecticides in D. melanogaster. Low levels of DDT insecticide resistance in field populations of D. melanogaster are influenced by the constitutive or inducible up-regulation of Cyp6g1 and Cyp12d1, 29,30 and microarray analysis indicated that DDT resistance is associated with over-transcription of Cyp6g1 in D. melanogaster.…”

Comparative physiology of Malpighian tubules: form and function

“…76 The gene encoding Cytochrome P450-4e3 (Cyp4e3) is upregulated in the principal cells of the MT in Drosophila fed on permethrin. 77 In MT of Drosophila, studies at the molecular level indicated the overexpression of a Cytochrome P450 gene, Cyp6g1, which has been evolved to insecticide resistance. 78 Catae et al 79 studied the effects of thiamethoxam in the midgut and MTs of the Apis mellifera honeybee.…”