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Vol. 56, Issue 1, 46-53, July 1999
Institut für Biochemie und Molekulare Zellbiologie,
Göttingen, Germany (T.K., K.J.); and Institut für
Pharmakologie und Toxikologie, Göttingen, Germany (K.I.H.-E.,
G.F.K.)
Treatment of male rats with phenobarbital (PB) results in a perivenous
and mid-zonal pattern of cytochrome P-450 (CYP)2B1 mRNA expression
within the liver acinus. The mechanism of this zonated induction
is still poorly understood. In this study sinusoidal gradients of
oxygen and epidermal growth factor (EGF) besides those of the
pituitary-dependent hormones growth hormone (GH), thyroxine (T4), and
triiodothyronine (T3) were considered to be possible determinants for
the zonated induction of the CYP2B1 gene in
liver. Moreover, heme proteins seem to play a key role in oxygen
sensing. Therefore, the influence of arterial (16% O2) and
venous (8% O2) oxygen tension (pO2),
and of the heme synthesis inhibitors CoCl2 and
desferrioxamine (DSF) on PB-dependent CYP2B1 mRNA induction as well as
the repression by EGF and, for comparison, by GH, T4, and T3, of the
induction under arterial and venous pO2 were investigated
in primary rat hepatocytes. Within 3 days, phenobarbital induced
CYP2B1 mRNA to maximal levels under arterial pO2 and to
about 40% of maximal levels under venous pO2.
CoCl2 annihilated induction by PB under both oxygen
tensions, whereas desferrioxamine and heme abolished the positive
modulation by O2, suggesting that heme is a necessary
component for O2 sensing. EGF suppressed CYP2B1 mRNA
induction by PB only under arterial but not under venous
pO2, whereas GH, T4, and T3 inhibited induction under both
arterial and venous pO2. Thus, in hepatocyte cultures, an
O2 gradient in conjunction with EGF mimicked the perivenous induction by PB of the CYP2B1 gene observed in the liver
in vivo.
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