Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals
- J. Christopher Corton1,2,
- Li-Qun Fan1,
- Sherri Brown1,
- Steven P. Anderson1,
- Carlos Bocos1,2,
- Russell C. Cattley1,
- Agneta Mode2 and
- Jan-Åke Gustafsson2
- 1Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709 (J.C.C., L.-Q.F., S.B., S.P.A., R.C.C.), and2Department of Medical Nutrition, Huddinge University Hospital, Novum S-141 86, Huddinge, Sweden (J.C.C., C.B., A.M., J.-A.G.)
Abstract
In this study, we show that peroxisome proliferator chemical (PPC) exposure leads to alterations in the expression of genes in rat liver regulated by the sex-specific growth hormone secretory pattern and induced during inflammation. Expression of the male-specificcytochrome P450 (P450) 2C11 and α2 urinary globulin (α2u) genes and the female-specificP450 2C12 gene was down-regulated by some PPC. Expression ofP450 2C13, also under control by the sex-specific growth hormone secretory pattern, was not altered by PPC treatment, indicating that regulation of CYP2C family members does not involve perturbation of the growth hormone secretory pattern. In contrast to the increases in expression observed when inflammation was induced in male rats, two positive acute-phase response genes, α1-acid glycoprotein and β-fibrinogen, were decreased by PPC exposure. The down-regulation of the P450 2C11 by WY-14,643 could be reproduced in cultured rat hepatocytes, indicating the down-regulation is a direct effect. Experiments in wild-type mice and mice that lacked a functional peroxisome proliferator-activated receptor-α gene showed that down-regulation by WY of α1-acid glycoprotein,β-fibrinogen, and a mouse homologue of α2uwas dependent on peroxisome proliferator-activated receptor-α expression. Our results demonstrate that PPC exposure leads to down-regulation of diverse liver-specific genes, includingCYP2C family members important in hormonal homeostasis and acute-phase response genes important in inflammatory responses.
Footnotes
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Send reprint requests to: Dr. Chris Corton, CIIT, P.O. Box 12137, 6 Davis Drive, Research Triangle Park, NC 27709. E-mail:corton{at}ciit.org
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↵1 Current affiliation: Facultad cle Ciencias Experimentales y Técnicas, Universidad San Pablo CEU, Urbanizaci-n Monteprı́ncipe 28668 Madrid, Spain.
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This work was supported in part by a grant from the Swedish Cancer Society.
- Abbreviations:
- PPC
- peroxisome proliferator chemical
- AGP
- α1-acid glycoprotein
- α2u
- α2urinary-globulin
- ACO
- acyl-coenzyme A oxidase
- DBP
- di-n-butyl phthalate
- DEHP
- di-(2-ethylhexyl)phthalate
- Fib
- fibrinogen
- GEM
- gemfibrozil
- GH
- growth hormone
- HNF
- hepatocyte nuclear factor
- MUP
- major urinary protein
- P450
- cytochrome P450
- PPAR
- peroxisome proliferator-activated receptor
- PPRE
- peroxisome proliferator response element
- SDS-PAGE
- sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- tNA
- total nucleic acids
- WY
- WY-14,643
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- Received April 27, 1998.
- Accepted May 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
