Genetic variation in cytochrome P-450 and xenobiotic metabolism in Drosophila melanogaster

Abstract

A marked genetic variation in the capacity to perform xenobiotic metabolism was observed in microsomal fractions from the seven Drosophila strains studied. A 1,5 to 2-fold variation was found in the content of cytochrome P-450 and in the NADPH-cytochrome c reductase activity. The two insecticide-resistant strains Hikone R and Oregon R differed markedly when compared to sensitive strains by having a 3 to 17-fold higher p-nitroanisole (PNA) demethylase activity and biphenyl-3-hydroxylase activity. SDS-polyacrylamide gel electrophoresis of the microsomes also revealed an increased content of a protein band with an apparent mol. wt of 54,000 in the resistant strains. The 4-hydroxylation of biphenyl was also 2–7-fold higher in the Oregon R strain, and the band with a mol. wt of 56,000 had a higher protein content compared to the other strains. The biphenyl-4-hydroxylation was several-fold lower in the strain Berlin K. 2-OH-biphenyl was formed only in trace amounts by all strains. 7-Ethoxycoumarin (EC) deethylase activity and benzo(a)pyrene (BP) monooxygenase activity was 2–6-fold lower in the Hikone R strain. An increased amount of the protein with a mol. wt of 58,000 was noted in the Canton S strain. No concomitant increase in any enzyme activity was observed. A genetic variation between the strains was observed after phenobarbital (PB) treatment in the content of cytochrome P-450 and in the various enzyme activities, varying from non-responsiveness to a 4- to 5-fold increase. Aroclor 1254 (PCB) was less efficient in enhancing the activities. It caused maximally a 3-fold increase, had often no effect and in some cases even decreased the metabolism. β-naphthoflavone (BNF) caused only marginal increases in the activities in most strains. The only significant effects were an increased formation of 3-OH-biphenyl in Berlin K and an enhanced NADPH-cytochrome c reductase activity in Lausanne-S. In conclusion, the variations observed in this study provide a basis for further studies on the genetic regulation of the cytochrome P-450 system in Drosophila. Furthermore, similarities in the regulation when compared to mammals indicate that studies on this genetically well characterized organism might contribute to the general understanding of the genetics of xenobiotic metabolism.