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Vol. 285, Issue 1, 127-134, April 1998
Unidad de Hepatología Experimental (M.I.G., M.T.D., R.J.,
J.V.C., M.J.G.-L.), Centro de Investigación, Hospital
Universitario La Fe, Valencia, Spain; and
Servicio de Cirugía
(R.F., R.T.), Hospital General de Valencia, Spain
The effects of oncostatin M on the expression of different cytochrome
P450 (CYP) isozymes has been investigated in human hepatocytes. The
dose-response and time-course analyses of effects on CYP1A2 and CYP3A4
isozymes revealed that maximal inhibition was reached after 48 hr of
exposure of human hepatocytes to 25 units/ml oncostatin M. Reductions
in CYP1A2 and CYP3A4 activity produced by oncostatin M correlated with
decreases in protein content, de novo protein synthesis and
specific mRNA levels, thus suggesting that oncostatin M could
down-regulate CYP expression at the transcriptional level. The
inhibitory potency of oncostatin M on CYP expression was compared with
that of other cytokines belonging to the interleukin-6 receptor family
(interleukin-6, interleukin-11 and leukemia inhibitory factor), and
interferon-
, which is recognized to inhibit human CYP expression,
and granulocyte colony-stimulating factor, a cytokine that shares
structural homology with the interleukin-6 family but has a different
transduction signal. Maximal reductions in CYP1A2 activity were reached
after 48 hr of treatment with cytokines. At that time, oncostatin M
showed the highest inhibitory effects on CYP1A2 activity (38% of
control), followed by interferon (49% of control) and interleukin-6
(60% of control), whereas minor effects were produced by the other
cytokines (74-80%). Comparable decreases were observed for CYP2A6,
CYP2B6 and CYP3A4 activities. Enzymatic activity and de novo
protein synthesis of 3-methylcholanthrene-induced CYP1A2 and
dexamethasone-induced CYP3A4 were also reduced to a much greater extent
by oncostatin M than by other cytokines. The results show that
oncostatin M is the most effective cytokine in down-regulating CYP
isozymes in human hepatocytes, and its effects were evident even after
removal of the cytokine from the culture medium.
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