Administration of
xenobiotics to rats results in
hypercholesterolemia and in the induction of 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) reductase and malic
enzyme. To investigate the mechanism of the induction of the
enzymes by
xenobiotics, the effects of
xenobiotics on gene expressions for
HMG-CoA reductase, malic
enzyme, and
cytochrome P-450 in rat liver and in cultured hepatocyte were investigated. The treatment of rats with
polychlorinated biphenyls (PCB) as a
xenobiotic induced mRNAs for
HMG-CoA reductase and malic
enzyme as well as
CYP2B1/2 (
cytochrome P-450b/e). Other
xenobiotics,
1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (
DDT), and
chloretone, also increased
HMG-CoA reductase mRNA. In an investigation of diurnal rhythm of
mRNA for
HMG-CoA reductase, the induction by PCB was observed in a dark period. Induced expressions of
HMG-CoA reductase gene and malic
enzyme gene by PCB were observed in primary cultured rat hepatocytes and showed that the action of PCB on the gene expression relating to lipid metabolism was directed on hepatocytes. The induction was observed only in hepatocytes cultured on
Engelbreth-Holm-Swarm sarcoma basement membrane gel (EHS-gel), not on
type I collagen, which is usually used for monolayer culture of hepatocytes. The induction of
CYP2B1/2 gene expression also was observed only in the cells cultured on EHS-gel. The induction of
HMG-CoA reductase and malic
enzyme by PCB required
dexamethasone. However, the addition of
dexamethasone per se to medium containing
insulin did not show an inductive effect on levels of
mRNA for
HMG-CoA reductase and malic
enzyme. From the data of diurnal variation and hepatocyte culture experiment,
HMG-CoA reductase and malic
enzyme are considered to be induced by PCB through the so-called "permissive effect" of
glucocorticoid.