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Vol. 63, Issue 4, 945-956, April 2003
Institut National de la Santé et de la Recherche
Médicale Unité-490, Centre Universitaire des
Saints-Pères, Paris, France (C.G., R.B., Y.M.); Centre
d'études du Bouchet, Vert-le Petit, France (N.K.B., Y.M.)
The human paraoxonase-1 (PON-1) is a serum high-density
lipoprotein-associated phosphotriesterase secreted mainly by the liver. This enzyme is able to hydrolyze toxic organophosphate xenobiotics, endogenous oxidized phospholipids, and homocysteine thiolactone. Physiologically, it is thought to protect against cardiovascular diseases. The level of PON-1 gene expression is a
major determinant of paraoxonase-1 status but little is known regarding
the regulation of this gene. We identified several transcription start
sites and characterized the regulation of its promoter by fibrates and statins. In HuH7 human hepatoma cells, the PON-1 secreted enzymatic activity and mRNA levels were increased by fenofibric acid
(approximately 70%) and decreased by several statins (approximately
50%). Transient and stable transfection assays in HuH7 cells indicated
that the modulation of the mRNA and enzymatic activity levels could be accounted for by the regulation of the PON-1 gene promoter activity by
these drugs. These effects are probably not mediated by the PPAR
because over-expression of this receptor decreased the fibrate effect
and did not modify statins activity. The repressive effect of statins
is reversed by mevalonate and 22(R)-hydroxycholesterol, suggesting the involvement of the liver X receptor in the mechanism. The opposite effects of fenofibrate and statins could be consistent with clinical data on homocysteine levels after hypolipidemic drug
treatment. Regarding the toxicological aspects, the induction achieved
with fenofibric acid, although limited, could increase organophosphate
metabolism and may be relevant in certain conditions for protective treatments.
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