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Vol. 289, Issue 2, 1121-1127, May 1999
Institute of Chemical Toxicology, Wayne State University, Detroit,
Michigan
Uncontrolled diabetes results in enhanced expression of cytochrome
P-450 (CYP)2E1, CYP2B, CYP3A, and CYP4A. Because of the simultaneous
and confounding metabolic and hormonal changes that occur in vivo as a
consequence of diabetes, primary cultured rat hepatocytes provide an
excellent model system for examination of the effects of insulin on
P-450 expression and on xenobiotic-mediated P-450 expression. In the
present study, we examined the effects of insulin on pyridine-,
phenobarbital-, and ciprofibrate-mediated expression of CYP2E1, CYP2B,
CYP3A, and CYP4A in primary cultured rat hepatocytes. Pyridine addition
to primary rat hepatocytes cultured in the presence of 1 nM insulin or
in the absence of insulin resulted in a 3.5-fold and 3-fold enhancement
in CYP2E1 protein expression, respectively, in the absence of any
pyridine-mediated increase in mRNA expression. In contrast, hepatocytes
cultured in the standard concentration of 1 µM insulin resulted in
only a 2-fold increase in protein expression. Thus, the fold-induction of CYP2E1 protein in response to pyridine was 1.5- to 1.8-fold greater
in either the absence of insulin or in the presence of 1 nM insulin,
respectively, than that monitored in the presence of 1 µM insulin. To
examine whether insulin effects on xenobiotic-mediated CYP2E1
expression were selective, insulin effects on xenobiotic-mediated expression of transcriptionally regulated CYP2B, CYP3A, and CYP4A were
examined. Pyridine- or phenobarbital-mediated induction of CYP2B mRNA
and protein expression in hepatocytes was suppressed by as much as 80%
at lower insulin levels (0 and 1 nM), relative to the level monitored
in the presence of 1 µM insulin. Omitting insulin from the medium
resulted in a 50% decrease in CYP3A mRNA levels in response to
phenobarbital treatment and a 30% decrease in CYP4A mRNA levels in
response to ciprofibrate treatment, relative to the level obtained in
response to these treatments in the presence of 1 µM insulin. The
results of this study demonstrate that decreasing the insulin level in
the primary hepatocyte culture medium enhanced xenobiotic-mediated
CYP2E1 expression, whereas lower insulin levels suppressed
xenobiotic-mediated CYP2B, CYP3A, and CYP4A expression in this cell
culture system.
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