Counterbalancing roles of two cytochrome P450 genes to aflatoxin B1, a naturally occurring xenobiotic in the diet of Drosophila melanogaster

Often, a single cytochrome P450 (P450) is implicated in the emergence of insecticide resistance in a population of insects and immediately labeled as a detoxification enzyme, without consideration for the multiple functions it may perform within the insect. In addition, little is known about the role of multiple P450s, concurrently expressed, that may interact, via their metabolites, to buffer or exacerbate toxic effects. Cyp6a2 is a P450, expressed in both larvae and adults, that detoxifies a number of insecticides (aldrin, heptachlor, DDT) but also bioactivates the fungal toxin aflatoxin B₁, a natural constituent of the larval diet. We have observed that, when Cyp6a2 is knocked down, as in the methoprene-tolerant strain Rst(1)JH¹, larvae develop more quickly on an aflatoxin-containing diet than the wildtype strain Oregon-R. Expression of Cyp6a2, as measured by reverse transcription PCR, is demonstrably higher in third instar Oregon-R than in Rst(1)JH¹. Analysis of the expression of additional P450s reveals that Cyp6d2 is induced in Oregon-R in the presence of aflatoxin B₁, and constitutively overexpressed in Rst(1)JH¹. Cyp6d2 may thus counteract the bioactivating effects of Cyp6a2 through its own detoxifying reaction. Ongoing studies on the metabolism of aflatoxin B₁ by CYP6A2 and CYP6D2 are addressing this question. Regardless of the mechanism, this study posits that Cyp6d2 may have evolved to serve as a counterbalance to the bioactivating functions of Cyp6a2 (and possibly other P450s) toward naturally occurring xenobiotics.