The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila.
Exposure to xenobiotics such as plant toxins, pollutants, or prescription drugs triggers a defense response, inducing genes that encode key detoxification enzymes. Although xenobiotic responses have been studied in vertebrates, little effort has been made to exploit a simple genetic system for characterizing the molecular basis of this coordinated transcriptional response. We show here that approximately 1000 transcripts are significantly affected by phenobarbital treatment in Drosophila. We also demonstrate that the Drosophila ortholog of the human SXR and CAR xenobiotic receptors, DHR96, plays a role in this response. A DHR96 null mutant displays increased sensitivity to the sedative effects of phenobarbital and the pesticide DDT as well as defects in the expression of many phenobarbital-regulated genes. Metabolic and stress-response genes are also controlled by DHR96, implicating its role in coordinating multiple response pathways. This work establishes a new model system for defining the genetic control of xenobiotic stress responses.
King-Jones
Kirst
K
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, 15 N 2030 E 5100, Salt Lake City, Utah 84112, USA.
Horner
Michael A
MA
Lam
Geanette
G
Thummel
Carl S
CS
D000818:Animals; D003634:DDT / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000187:drug effects / Q000378:metabolism*; D029721:Drosophila Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D009154:Mutation; D010634:Phenobarbital / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015262:Xenobiotics / Q000494:pharmacology
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C096796:Hr96 protein, Drosophila; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015262:Xenobiotics; D003634:DDT; D010634:Phenobarbital