Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD).
OBJECTIVE
The aim of the current study was to investigate the species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD) in relation to activation of CAR.


METHODS
7-Pentoxyresorufin O-dealkylase (PROD) activity, RT-PCR, Western blot, Electrophoretic mobility shift assays (EMSA).


RESULTS
Phenobarbital-like inducer administration significantly up-regulated CYP2B activity in rat and mouse liver in a species-specific manner, in contrast to the effects on CYP2B in lungs, kidneys and brains. In parallel, Western blot analysis showed that the species-specific increase of PROD in liver is related to the high content of CYP2B: phenobarbital (PB) and TPD increased CYP2B in rat liver, PB and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) - in mouse liver. The CYP2B protein level was unchanged in the lungs of rats and mice after inducer treatment, whereas it was not detected in the kidney and brain of control and treated animals. The hepatic CYP2B activity in both species paralleled the increase of CYP2B mRNA. A detectable CYP2B mRNA level was measured in the lungs of untreated mice and rats, though it was unchanged during induction. Noninducibility of CYP2B in extrahepatic tissues accompanied an absence of constitutive androstane receptor (CAR) gene expression in these tissues. In liver CYP2B induction paralleled the high level of CAR expression detected by RT-PCR. Moreover, PB, TPD and TCPOBOP treatment stimulated nuclear accumulation of CAR and increased CAR receptor NR1-binding activity in animal liver in a species-specific manner.


CONCLUSIONS
We have shown that the increased nuclear accumulation and binding activity of CAR are associated with the species-specific up-regulation of CYP2B by TPD in rat liver.
Pustylnyak
Vladimir
V
Institute of Molecular Biology and Biophysics, Novosibirsk State University, Russian Federation. pustylnyak@ngs.ru
Pivovarova
Elena
E
Slynko
Nikolai
N
Gulyaeva
Lyudmila
L
Lyakhovich
Vyacheslav
V
D000818:Animals; D015153:Blotting, Western; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004146:Dioxanes / Q000737:chemistry / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D018076:DNA, Complementary; D004146:Dioxanes; D020536:Enzyme Activators; C054589:2,4,6-triphenyl-1,3-dioxane; D019362:Cytochrome P-450 CYP2B1