The 4S benzo(a)pyrene-binding protein is not a transcriptional activator of Cyp1a1 gene in Ah receptor-deficient (AHR -/-) transgenic mice.
In an effort to better understand the role of the 4S benzo(a)pyrene-binding protein in the induction of CYP1A1 by PAHs, we used a genetically engineered mouse line deficient in Ah receptor (AHR -/-). First, we demonstrated through binding experiments analyzed by sucrose gradient sedimentation and gel permeation chromatography that AHR -/- mice have no detectable AHR protein. In contrast, this AHR-deficient line expressed a 4S protein which efficiently binds BP as it does in hepatic cytosol from C57BL/6 mice. In vivo BP exposure in AHR-deficient mice proved the inability to sustain any CYP1A1 mRNA or CYP1A1 protein induction. These findings demonstrate the requirement of an active AHR to sustain the transactivation pathway leading to CYP1A1 induction. Surprisingly, the 4S BP-binding protein, which was previously characterized as the glycine N-methyltransferase, was completely devoid of such an enzymatic activity after purification by Sephacryl gel permeation chromatography. Moreover, sedimentation and chromatographic experiments, under nondenaturing conditions, do not support the assumption of 4S protein as a subunit of a multimeric protein (GNMT) displaying a molecular mass of 150 kDa.
Foussat
J
J
Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, Toulouse, France.
Costet
P
P
Galtier
P
P
Pineau
T
T
Lesca
P
P
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators
C488945:4S benzo(a)pyrene-binding protein, mouse; D002352:Carrier Proteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; C032445:benzopyrene carrier protein, mouse; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1