Abstract
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 PPARα 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.
Footnotes
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This work was supported by the Délégation Générale pour l'Armement (DGA/STTC contract 99 CO 099), Université René Descartes, and Région Ile de France. C.G. has a Délégation Générale pour l'Armement–Centre National de la Recherche Scientifique grant.
- Abbreviations:
- HDL
- high-density lipoprotein
- OP
- organophosphate
- LDL
- low-density lipoprotein
- OD
- optical density
- FCS
- fetal calf serum
- RT-PCR
- reverse transcriptase-mediated polymerase chain reaction
- G3PDH
- glucose-3-phosphate deshydrogenase
- PPRE
- peroxisome proliferator responsive element
- PPAR
- peroxisome proliferator-activated receptor
- CMV
- cytomegalovirus
- kb
- kilobase(s)
- WY-14643
- (4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl)thioacetic acid
- HMG
- 3-hydroxy-3-methylglutaryl
- LXR
- liver X receptor
- LXRE
- liver X receptor response element
- Hcy
- homocysteine
- DMSO
- dimethyl sulfoxide
- DR
- direct repeat
- Apo
- apolipoprotein
- Received June 3, 2002.
- Accepted January 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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