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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pestic Biochem Physiol. Author manuscript; available in PMC Jun 1, 2011.
Published in final edited form as:
Pestic Biochem Physiol. Jun 1, 2010; 97(2): 115–122.
doi:  10.1016/j.pestbp.2009.06.009
PMCID: PMC2890303

Regulation of cytochrome P450 expression in Drosophila: Genomic insights


Genomic tools such as the availability of the Drosophila genome sequence, the relative ease of stable transformation, and DNA microarrays have made the fruit fly a powerful model in insecticide toxicology research. We have used transgenic promoter-GFP constructs to document the detailed pattern of induced Cyp6a2 gene expression in larval and adult Drosophila tissues. We also compared various insecticides and xenobiotics for their ability to induce this cytochrome P450 gene, and show that the pattern of Cyp6a2 inducibility is comparable to that of vertebrate CYP2B genes, and different from that of vertebrate CYP1A genes, suggesting a degree of evolutionary conservation for the “phenobarbital-type” induction mechanism. Our results are compared to the increasingly diverse reports on P450 induction that can be gleaned from whole genome or from “detox” microarray experiments in Drosophila. These suggest that only a third of the genomic repertoire of CYP genes is inducible by xenobiotics, and that there are distinct subsets of inducers / induced genes, suggesting multiple xenobiotic transduction mechanisms. A relationship between induction and resistance is not supported by expression data from the literature. The relative abundance of expression data now available is in contrast to the paucity of studies on functional expression of P450 enzymes, and this remains a challenge for our understanding of the toxicokinetic aspects of insecticide action.

1. Introduction

Insecticidal action requires the presence of an active form of the insecticide at the target site at an effective concentration and for a sufficient time. The determinants of this bioavailability, transport, metabolism and sequestration, are therefore the toxicokinetic parameters [1] in insecticidal action. They have an equal importance to the molecular details of toxicodynamic, or mode of action, parameters. Efficacy, selective toxicity, and resistance can all be determined by either toxicokinetic or toxicodynamic differences between a sensitive species and a less sensitive species, a target or a non-target organism, and a susceptible or a resistant strain.

The increased use of Drosophila as a model insect in toxicology studies over the last decade is a logical consequence of the advantages it offers [2, 3]. In the specific area of insecticide metabolism and resistance, the Drosophila genome sequence provided a first complete picture of cytochrome P450 diversity and abundance in insects with about 85 active CYP genes [4] while other insect genomes harbor more or fewer CYP genes [5]. The genomic tools available in Drosophila now allow both the detailed study of single genes and global approaches on the whole family of P450s in an insect.

Here, we provide examples of both approaches. First we focus on the Cyp6a2 gene, a gene abundantly expressed in insecticide-resistant strains [69]. The CYP6A2 enzyme metabolizes organochlorine and organophosphorus insecticides [10] as well as dimethylbenzanthracene and aflatoxin B1 [11]. A mutant form of CYP6A2 has been reported to metabolize DDT as well [12]. The detoxification function of CYP6A2 is thus well established. Cyp6a2 is also known to be inducible by barbiturates [7, 9, 10, 13]. We report here the fine-scale mapping of the tissues in which the Cyp6a2 gene is induced, and we report the pattern of Cyp6a2 induction by various classes of chemicals using a screening approach with a transgenic GFP marker.

Secondly, we analyze the literature for induction of other CYP genes in Drosophila in order to place Cyp6a2 in the context of the whole CYP family. The use of DNA microarrays allowed a genome-wide or “CYPome”-wide assessment of transcript abundance, and many important studies have been published since this field was reviewed [14]. Our analysis shows that only a third of the genomic repertoire of CYP genes is inducible by xenobiotics, and that there are distinct subsets of inducers / induced genes, suggesting multiple xenobiotic transduction mechanisms.

2. Materials and methods

2.1 Transgenic Drosophila

The 1.3 kb promoter fragment of the Cyp6a2 gene [10] was cloned upstream of the Green Fluorescent Protein coding sequence in the pCasper P-element vector and this was used to transform the w1119 line of Drosophila melanogaster. The P[w+-1.3-Cyp6a2-GFP]-transformed lines were screened for high inducibility of GFP fluorescence following phenobarbital treatment. A double X-chromosome transformant line 1E; 11B;Sco/SM6b was used for further study.

2.2 CYP6A2-GFP induction

Induction of Cyp6a2-GFP by phenobarbital and by the polychlorobiphenyl mixture Aroclor 1254 (PCB) in different tissues/organs in larva, pupa and adult of the transgenic stock 1E; 11B;Sco/SM6b was determined using confocal microscopy. Late first instar or early second instar larvae, and 1-day-old adults were fed for 3–5 days on Ward’s Drosophila instant diet mixed with phenobarbital (1g dry instant diet + 2.5ml 0.4% phenobarbital sodium in distilled water). One-day-old flies were also treated with PCB, by contact for 4–5 days; for this, 15–20 flies were kept in 20ml glass scintillation vials coated with 0.1mg (3µg/cm2) PCB dissolved in acetone. PCB-treated flies were also fed wet instant diet placed at the bottom of the vial. For controls, larvae and adults were similarly but without phenobarbital sodium or PCB. Whole larvae after molting in to 2nd or 3rd instar, and adults, and freshly dissected organs from larvae and adults were mounted on microscope slide in 80% glycerin in PBS and were examined for GFP fluorescence using a laser scanning confocal microscope (BioRad 1024 confocal scanning head attached to a Nikon Optiphot 2 microscope with PlanApo objectives). Confocal images were processed, using Lasersharp software (BioRad, Hercules, CA) and Adobe Photoshop. Treatment of flies with other chemicals was either by contact (DDD:0.1 mg/vial; DDE:0.01 mg/vial; dicofol: 0.1mg/vial; aldrin: 1 µg/vial; clofibrate: 10 µg/vial) or by incorporation in the media i.e. ingestion (trans-stilbene oxide: 0.3%; limonene: 0.1%)

3. Results

3.1 Tissue specificity of Cyp6a2-GFP induction

Cyp6a2-GFP fluorescence was induced in many but not all the tissues/organs in treated larvae and adults (Table 1). In addition to this non-ubiquitous expression, there were also apparent quantitative differences among different tissues/organs. Yellow/orange auto-fluorescence of chitinous cuticle and cuticular lining of internal structures (trachea, crop, foregut, proventriculus/cardia, hindgut, rectum, salivary gland duct), food content (digestive system), or other inclusions (distal part of the Malpighian tubules, nephrocytes and pericardial cells) sometimes masked or modified the green fluorescence (GF). All muscles/ muscle fibers in both larvae and adults showed GF, but in the flight muscles GF was less intense than in other muscular components. Heart also showed only weak GF. In adults, regions of the body covered with only the membranous cuticle showed uniform green fluorescence because of the GFP in hemolymph (hemocytes) and epidermis. The fat body and the entire intestinal wall were intensely green fluorescent, but not the gastric caecum. GFP appeared to be induced throughout the central and peripheral nervous system, and sensory cells and their axons; but GF was weak in the larval brain and ganglion. In adult brain and ganglion, GF was more intense in the neuropile and lamina of the optic lobes than in the neurons. The ring gland and ovary did not show detectable GF, however, accessory glands showed faint GF. In the newly formed pupa, produced from phenobarbital-fed larva, fat body and digestive system were green (Fig.1 L); other internal structures were not distinguishable in whole-mounted pupae examined. None of the tissues/organs in control larvae, pupae and adult flies showed green fluorescence (Fig. 1. J, K & M, Fig. 2. L–N).

Fig. 1
Phenobarbital-induced GFP in third instar larva and pupa. A: Early third instar larva. B: Brain-ganglion complex and anterior part of the digestive system. and C: Abdominal region showing body wall and internal organs. D and E: anterior and posterior ...
Fig. 2
Phenobarbital (Pheno)- or PCB-treated adults. A: Female fly (Pheno). B and C: Apex of proboscis (frontal view), surface and interior (PCB). D: Brain, thoracic ganglion and anterior region of the digestive system (Pheno). E: Part of midgut and hindgut ...
Table 1
PCB / Phenobarbital- induced GFP in various tissues/organs in larvae and adults

3.2. Cyp6a2 induction by xenobiotics

The clear difference in green fluorescence between induced and non-induced insects allowed us to screen for the ability of various chemicals to induce Cyp6a2. Table 2 shows the response of the Cyp6a2-GFP transgenic line to treatment by various chemicals, compared to the induction pattern of vertebrate CYP1A and CYP2B genes [1517]. Phenobarbital, pentobarbital, organochlorines (DDT and aldrin), trans-stilbene oxide and limonene were all inducers of Cyp6a2 and these are known inducers of the CYP2B genes, but not of the CYP1A genes. In contrast, Cyp6a2 was not inducible by β-naphthoflavone or 3-methylcholanthrene, known inducers of the CYP1A genes. The case of polychlorobiphenyls is particularly interesting, as a mixture of coplanar and non-coplanar PCBs (Aroclor 1254) induces all three types of genes, but pure isomers show a distinguishable pattern: 2,4,5,2’,4’,5’-HCB (non-coplanar) induces Cyp6a2 and the CYP2B genes, but 3,4,5,3’,4’,5’-HCB (coplanar) only induces the CYP1A genes [18, 19]. Ethanol and clofibrate, typical inducers of the vertebrate CYP2E and CYP4A genes respectively did not induce Cyp6a2.

Table 2
Inducers of mammalian CYP1A and CYP2B genes compared with inducers of fruit fly Cyp6a2.

3.3. From Cyp6a2 induction to induction of the CYP-ome

Cyp6a2 was initially reported to be phenobarbital (or barbital) inducible, and it is also regulated by ecdysone [20]. It has recently been shown to be also induced by caffeine [21]. Moreover, a number of DNA microarray studies have now identified Cyp6a2 as being responsive to chemical treatments. We have therefore compared and evaluated the results of ten published studies from 17 datasets on xenobiotic treatment of Drosophila melanogaster that used either custom DNA arrays (“detox chips” [22,23]) or whole [2428] (and partial [2931]) genome arrays (Table 3). These studies covered ten chemicals, with different treatment regimes (concentrations and exposure times), as well as different developmental stages (third instar larvae and adults). Despite the differences in techniques and statistical treatments, we feel that the consensus outcome of this comparison provides an interesting first glimpse of the patterns of xenobiotic response of the fruit fly. Negative results, i.e. chemical treatments that did not induce P450 genes were not considered, although these are also informative [22]. We included the studies on exposure to Piper nigrum extracts [30] because the main component piperamides are well known. We did not include the study on dietary shift in larvae (standard cornmeal to bananas) [32] that showed a slight induction of Cyp9b2 and a moderate decrease in Cyp6g1 and Cyp4d2 expression. It is known that P450 genes are involved in the adaptation to diet in other Drosophila species, for instance Cyp28a1 and Cyp4d10 in D. mettleri [33], and that the transcriptome is affected by starvation. Every diet should be considered as a collection of inducers and inhibitors of various potencies and concentrations, but here we focus on identified xenobiotics.

Table 3
Induction of the CYPome

The results of this survey show that between one and twelve CYP genes are affected by each chemical treatment, and that no more than a third (27 P450s) of the CYP-ome is responsive to xenobiotics. Different classes of compounds induce different CYP genes, and there is considerable overlap between some chemicals while others stand out (Figure 3). For instance, paraquat (11 genes) and tunicamycin (7 genes) seem to induce a set of CYP genes with little overlap with the set induced by the other chemicals. Tunicamycin causes a stress at the level of the endoplasmic reticulum and paraquat causes stress through the generation of reactive oxygen species [26]. The CYP genes seen induced in those treatments are perhaps best described as stress-responsive. Cyp6d4, Cyp28a5 and Cyp4p1 are the common genes in that category. A broader overlap is seen in the response to the other chemicals, with 11 genes retained in the consensus for phenobarbital induction (from six experimental conditions), 12 genes for piperonyl butoxide and 11 genes for caffeine. Piper nigrum extracts, atrazine and pyrethrum induced fewer genes, whereas DDT and ethanol had only one major target in the CYPome (Cyp12d1 and Cyp6a8 respectively). Those common genes responding to a chemical challenge are Cyp6a2, Cyp12d1, Cyp6a8, Cyp6d5 and Cyp6w1. The wide chemical responsiveness of Cyp6a2 that we observed using the transgenic fly model is thus confirmed by the various microarray studies.

Fig. 3
Venn diagram summarizing the inducibility of Drosophila CYP genes by various chemicals. 1: ethanol; 2: pyrethrum; 3: phenobarbital; 4: caffeine; 5: piperonyl butoxide ; 6: Piper nigrum extract ; 7: atrazine; 8: tunicamycin ; 9: paraquat. The limited overlap ...

3.4 Induction and insecticide resistance

Several reports in the literature have noted that CYP genes that are constitutively overexpressed in insecticide-resistant strains are also inducible by xenobiotics in susceptible strains, in Drosophila and in other insect species. We thus compared the data on CYP gene induction by xenobiotics that were collected in DNA microarray experiments with the list of genes that are currently known to be constitutively overexpressed in resistant strains or otherwise related to resistance (Fig. 4). Of the 27 genes known to be inducible by one or the other xenobiotics, and of the 12 genes known to be associated with resistance, eight are overlapping. Of these eight only three (Cyp6a2, Cyp6g1 and Cyp12d1) have been shown to be causally related to resistance. Two (Cyp12a4 and Cyp6g2) have been experimentally linked to resistance but have not been shown to be inducible by any of the nine compounds tested to date.

Fig. 4
Venn diagram showing the overlap between CYP genes inducible by chemicals and CYP genes associated to resistance in field or laboratory studies. The overlapping genes are identified, and of those, the three genes that have been causally linked to resistance ...

4. Discussion and conclusions

4.1. Tissue-specific expression

The midgut, Malphighian tubules and fat body are the tissues recognized as the major sites of P450-mediated detoxification in insects [3436]. DNA microarray analyses in Drosophila have confirmed that P450 transcripts are enriched in these tissues. In Malphighian tubules of adult flies, the Cyp6a18 transcript was enriched >25 fold and Cyp6a2 enriched 8 fold [37]. The data of that study reveal that while 1,457 genes (10% of all genes) are expressed more than 2-fold in the Malphighian tubules, 29 P450 genes (or 28% of all P450 genes) are expressed over 2.8 fold. Similarly, 36 P450 genes (40%), including Cyp6a2, are represented in the larval midgut transcriptome [38]. A distillation of FlyAtlas data on tissue expression of P450 genes [39] shows that Cyp6a2 is not expressed at high levels in normal flies, with Malpighian tubules, hindgut and head being the major sites of expression. Our results also show that Cyp6a2 basal expression is very low, although our technique does not measure the Cyp6a2 transcript levels but the accumulation of GFP protein driven by the Cyp6a2 promoter, and is therefore qualitatively different and perhaps less sensitive. Following induction, however, the gene is highly expressed both in larvae and in adults, in the midgut, Malpighian tubules and fat body. These results confirm and expand in detail the early results obtained by in situ hybridization in adult flies [7]. They also clearly show that Cyp6a2, after induction, is expressed in many other tissues as well as in the recognized sites of detoxification. The expression in the nervous system, in both larvae and adults is of significance, as the majority of insecticides have nervous system targets, such as the organophosphorus insecticides that are metabolized by CYP6A2 [10]. Expression of CYP6D1 in the thoracic ganglia of adult house flies has also been reported to contribute to cypermethrin resistance in the Lpr strain [40]. The metabolism of xenobiotics by P450 enzymes is highly [double less-than sign] uncoupled [dbl greater-than sign], costing much NADPH and generating considerable amounts of reactive oxygen species, as shown recently in a detailed study of house fly CYP6A1 [53]. The uninduced, low basal production of P450 enzymes is therefore probably an optimal state in the absence of chemical challenge. The observation that induced Cyp6a2 should be found in a wide variety of tissues, beyond those in the front line of defense against xenobiotics such as the midgut and Malpighian tubules, may be an evolved response of insects who lack a closed circulatory system and therefore have all their tissues exposed to xenobiotics, once these have crossed the midgut or integument barriers.Cyp6a2 has a pattern of expression that is similar to that of Cyp6g1. Chung et al [50] have used in situ hybridization as well as GFP reporter constructs to study the spatial expression of the Cyp6g1 gene. They showed that the wild-type Cyp6g1 is expressed in parts of the midgut and in the Malpighian tubules. In wandering larvae, expression is also detected in the fat body. In resistant strains carrying a fragment of the Accord transposable element, the expression is higher in those tissues, the whole midgut, and also includes the gastric caeca. Manipulation (RNAi or overexpression) of Cyp6g1 transcript levels in transgenic flies under the control of a Malpighian tubule promoter is sufficient to affect DDT resistance, whereas RNAi suppression of Cyp6g1 expression in fat body or brain is without effect [39]. Thus, the tissue expression pattern is critical in determining the toxicodynamics of insecticides (or more generally xenobiotics) that are metabolized by P450 enzymes.

4.2 Specificity of induction

The Cyp6a2 gene appears to be responding to multiple chemical challenges, but not to all chemical treatments. Other genes in the CYPome also appear to have a specific range of response. It is obvious that the detailed study of one gene or the cursory analysis of the whole CYPome as seen through various microarray experiments does not allow definitive conclusions to be drawn, and that more detailed analyses should focus on the time course of induction and its dose response (see [22] for time courses). Nonetheless, it seems that about a third of the CYPome is inducible, while the majority of P450 genes is not regulated by xenobiotic exposure. The non-inducible genes probably include the Halloween genes encoding enzymes of ecdysteroid biosynthesis [41] but also include many genes of unknown function, that are expressed at low levels in the whole insect and may in fact have a very restricted physiological function and pattern of expression. Among the inducible genes, there are obvious subsets, evidenced in our survey as stress responsive genes and genes responding to chemical challenge. This suggests that the chemical diversity of xenobiotics is perceived by different, probably overlapping transduction mechanisms, and this leads to an adapted response. In vertebrates, this is achieved by two types of receptors, the members of the nuclear receptor family including the xenosensors PXR and CAR, and the bHLH-PAS proteins such as the Ah receptor. Cross-talk between these receptors and with receptors for endogenous hormones probably allows a fine-tuning of the response [42].

The inducibility of certain P450 genes in bacteria, plants, and insects by phenobarbital remains somewhat mysterious. However, the remarkable parallel between Cyp6a2 induction and the known induction pattern of mammalian CYP2B genes strongly suggests that the “phenobarbital-type” induction in insects and mammals may share some characteristic that has been conserved during evolution. The nuclear receptor CAR is an essential component of the mouse response to the drug [43; 44]. Analysis of the evolutionary relationships between Drosophila, Caenorhabditis elegans and vertebrate nuclear receptors revealed that the orphan receptor DHR96 was most closely related to the nematode NHR-8 and DAF-12 receptors and to vertebrate CAR, vitamin D receptor (VDR) and Pregnane X receptor (PXR) [45,46]. The nematode NHR-8 receptor is essential for wild-type resistance to colchicine and chloroquine [45]. Recently, King-Jones et al. [24] presented evidence for the role of DHR96 in the response of Drosophila to phenobarbital. They obtained DHR96 null mutants and showed that the expression of some but not all phenobarbital-inducible genes was affected in the mutants.

We attempted to silence the DHR96 gene by RNAi, using the UAS-GAL4 system wherein a transgenic line with a promoter driven-GAL4 expression was crossed to a transgenic line with UAS-driven expression of DHR96 dsRNA (line 11783R-2 kindly provided by Dr. Ueno, NIG-Fly, Japan). The heat shock promoter (hsp70-GAL4) or the promoter with moderate expression from the Cyp6g1 gene (Cyp6g1-GAL4; line kindly provided by Dr. ffrench-Constant, Univ. Exeter) were insufficient as drivers to obtain significant downregulation of DHR96, whereas a stronger, ubiquitous promoter (tubulin-GAL4) led to high mortality in both male and female crosses (results not shown). These negative results nonetheless indicate a complex role for DHR96 that may be involved in essential physiological or developmental process in addition to its reported implication in the response to xenobiotics.

4.3 Resistance and induction

Cyp6a2 and Cyp12d1 are both inducible by at least 4 compounds and their constitutive overexpression has been causally linked to resistance. CYP6A2 metabolizes organophosphorus insecticides [10] and CYP12D1, when overexpressed in transgenic flies, confers resistance to dicyclanil and to DDT [47]. We note here that Cyp12d1 is a recently duplicated gene (i.e. Cyp12d1 and Cyp12d2 that differ by only three non-neutral nucleotide changes (http://p450.sophia.inra.fr), Cyp12d2 having been masked by a gap in the initial release of the Drosophila genome sequence). A third gene, Cyp6g1, is inducible by phenobarbital and by caffeine, and its overexpression in natural populations of Drosophila [48, 49] as well as in transgenic flies [48, 50, 47, 39] causes resistance to DDT and to neonicotinoids. Five other genes, Cyp4e2, Cyp4p1, Cyp6a17, Cyp6a8 and Cyp6w1 are both inducible and overexpressed in some resistant strains, but there is no evidence for their causal relationship to resistance. The case of Cyp6a8 is noteworthy, as the recombinant enzyme metabolizes aldrin to a modest degree but not heptachlor or DDT [51], and its overexpression in transgenic flies does not confer resistance to DDT, nitenpyram, dicyclanil or diazinon [47]. Two genes are known to be linked to resistance but have not been shown to be inducible in any of the studies that we analyzed. Cyp12a4 confers a selective resistance to lufenuron in field strains and in laboratory, transgenic strains [52]. Cyp6g2 is a gene expressed at very low levels in the head [39] but its transgenic overexpression in gut and Malpighian tubules confers diazinon and dicyclanil resistance [47]. These discrepancies highlight the danger of associating resistance with constitutive overexpression, and resistance with induction. We have argued [23] that inducibility of a P450 gene implies the presence of cis-regulatory sequences in addition to the sequences controlling the correct tissue and developmental expression. The broader target (cis-sequences of the induced gene and genes for the trans-factors that are necessary for its induction) for mutational events is therefore a risk factor for resistance when the gene encodes a xenobiotic-metabolizing enzyme. It is well known that inducibility is under genetic control with different insect strains showing different induction patterns (see e.g. [5456]). Hällström [57] has compared a resistant strain in which the resistance mutation has caused increased constitutive expression and has abolished further inducibility to a “constitutive mutant”. Any other link between induction and resistance is probably coincidental rather than causal, because the time needed for induction and its dose-response would not sufficiently improve the toxicokinetics of most fast-acting neurotoxins used as insecticides to explain resistance.

While this paper was under review, Chung et al. [58] reported on the constitutive expression of CYP genes in Drosophila larvae. They obtained expression patterns for about two thirds of the CYPome, of which half were expressed in the fat body, midgut and Malpighian tubules, including all the genes that we highlighted in Figure 3. Many other genes had a more discrete expression pattern, sometimes specific to small organs or cell types. Their results and our survey lead to a similar conclusion, that only a restricted subset of P450 enzymes are likely to be involved in detoxification. Many endogenous functions remain to be discovered for the other P450 enzymes.


Work on Cyp6a2-GFP was supported by National Institutes of Health grants GM39014 and ES06694. We thank Dr. Ueno and Dr. ffrench-Constant for the UAS or GAL4 transgenic lines. We thank B. Dunkov for help with the GFP transgenic lines and the Synthetic Core Facility, Southwest Environmental Health Sciences Center, University of Arizona, for the hexachlorobiphenyls.


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