Down-regulation of cytochrome P450 2C family members and positive acute-phase response gene expression by peroxisome proliferator chemicals.
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-specific cytochrome P450 (P450) 2C11 and alpha2 urinary globulin (alpha2u) genes and the female-specific P450 2C12 gene was down-regulated by some PPC. Expression of P450 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, alpha1-acid glycoprotein and beta-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-alpha gene showed that down-regulation by WY of alpha1-acid glycoprotein, beta-fibrinogen, and a mouse homologue of alpha2u was dependent on peroxisome proliferator-activated receptor-alpha expression. Our results demonstrate that PPC exposure leads to down-regulation of diverse liver-specific genes, including CYP2C family members important in hormonal homeostasis and acute-phase response genes important in inflammatory responses.
Corton
J C
JC
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA. corton@ciit.org
Fan
L Q
LQ
Brown
S
S
Anderson
S P
SP
Bocos
C
C
Cattley
R C
RC
Mode
A
A
Gustafsson
J A
JA
D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000201:enzymology* / Q000235:genetics*; D000510:Alpha-Globulins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology
D000209:Acute-Phase Proteins; D000510:Alpha-Globulins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C013803:alpha 2u globulin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase