The Toxicologist - Society of Toxicology

OA did not affect food consumption. BHA in standard chow significantly decreased
body weight. The LD did not increase body weight alone, but significantly
increased body weight when administered in combination with BHA or OA. BHA
in standard chow increased liver weight, but OA did not. The LD significantly increased
liver weight by 50%, with the BHA addition increasing liver weight an additional
50% more than the LD alone. Liver weight was increased to a similar degree
in mice that received LD diet alone or in combination with OA compared to
the standard diet. The LD increased serum cholesterol by 47% compared to the
standard diet. BHA in combination with the LD markedly increased serum cholesterol
levels 2 fold higher compared to LD alone. OA in combination with the LD
increased serum cholesterol levels by 15%. Together the data demonstrate that Nrf2
activators increased liver weight along with serum cholesterol levels when combined
with a high cholesterol diet. (NIH 5K22ES013782, 3R01ES016042-02S1).
1117 BERBERINE INDUCES HEPATIC STEATOSIS VIA
C/EBPβ ACTIVATION.
B. Lee 1 , Y. Choi 1 , H. Suh 1 , S. Jeoung 1 and K. Lee 2 . 1 Seoul National University,
Seoul, Republic of Korea and 2 Sungkyunkwan University, Suwon, Republic of Korea.
Berberine (BBR) is a isoquinoline alkaloid with wide potential therapeutic properties
against diabetic and obesity. BBR improves lipid metabolism in obese and diabetic
rodent models via activation of AMP-activated protein kinase. However, the
hepatotoxicity of BBR in terms of the hepatic lipid metabolism is not clearly understood.
Here we show that BBR increased fatty acid uptake and caused lipid accumulation
in HepG2 cells. BBR treatment induced lipid accumulation in HepG2
cells as determined by nile red staining. BBR stimulated CCAAT/enhancer-binding
protein β (C/EBPβ) expression in a dose-dependent manner and its downstream
molecule peroxisome proliferator-activated receptor γ and CD36 was also increased.
Upregulation of CD36, a fatty acid transporter, induced by BBR facilitated
the uptake of fatty acid determined by BODIPY-C16. Conversely, C/EBPβ RNA
interference attenuated BBR-induced lipid accumulation and uptake of fatty acid.
These data provide evidence that BBR can cause fatty liver disease mediated by
C/EBPβ.
1118 EFFECTS OF MEDICINAL HERBS AND THEIR
COMPONENTS ON THE STEATOGENIC
HEPATOTOXICITY.
Y. Choi 1 , S. Jeoung 1 , H. Suh 1 , H. Choi 1 , S. Park 1 , S. Oh 1 , J. Choi 2 , S. Lee 3 ,
K. Lee 4 and B. Lee 1 . 1 Seoul National University, Seoul, Republic of Korea, 2 Pukyong
National University, Pusan, Republic of Korea, 3 Yeungnam University, Gyeongbuk,
Republic of Korea and 4 Sungkyunkwan University, Suwon, Republic of Korea.
Herbal medicine is widely used in many countries for the treatment of many diseases.
Although the use of herbal extract as alternative medicine is even growing,
their toxicological properties have not been thoroughly investigated. In this study,
we investigated the effect of water and ethanol extracts of 10 herbs on the hepatic
lipid metabolism causing steatogenic hepatotoxicity. Ethanol extracts of Cirsium
japonicum, Casthamus tincorius and Corydalis ternata Nakai induced the lipid accumulation
in Sk-hep1 human hepatoma cells as determined by nile red staining.
They increased the luciferase activity of SRE and decreased that of PPRE, indicating
the possibility of the enhanced fatty acid synthesis along with the decreased fatty
acid oxidation. To identify the components responsible for the fat accumulation, we
tested 12 chemicals isolated from the three herbs, apigenin, luteolin, pectolinarin
and lupeol from Cirsium japonicum, carthamin, terpinene, camphor and terpineol
from Casthamus tincorius and canadine, tetrahydrocoptisine, thalifendine and
berberine from Corydalis ternata Nakai increased the accumulation of lipid droplet
significantly. These results suggest that ethanol extracts of Cirsium japonicum,
Casthamus tincorius and Corydalis ternata Nakai can cause fatty liver disease and it
is mediated by decrease of β-oxidation of fatty acid and increase of lipogenesis.
1119 FIBRINOGEN DEFICIENCY INCREASES LIVER INJURY
AND EARLY GROWTH RESPONSE-1 EXPRESSION IN A
MODEL OF CHRONIC XENOBIOTIC-INDUCED
CHOLESTASIS.
J. P. Luyendyk 1 , K. M. Kassel 1 , K. Allen 1 , G. L. Guo 1 , G. Li 1 , G. H. Cantor 2
and B. L. Copple 1 . 1 Pharmacology, Toxicology and Therapeutics, The University of
Kansas Medical Center, Kansas City, KS and 2 Discovery Toxicology, Bristol-Myers
Squibb, Princeton, NJ.
Chronic cholestatic liver injury is associated with hepatic fibrin deposition. Key
components of the fibrinolytic pathway modulate cholestatic liver injury by regulating
activation of hepatocyte growth factor (HGF). However, the exact role of he-
patic fibrin deposition in chronic cholestasis is not known. We tested the hypothesis
that hepatic fibrin limits liver injury induced by cholestasis. Fibrinogen (Fbg)deficient
mice (Fbgα-/- mice) and heterozygous control mice (Fbgα+/- mice) were
fed either control diet, or a diet containing 0.025% alpha-naphthylisothiocyanate
(ANIT), which selectively injures bile duct epithelial cells in the liver, for two
weeks. Hepatic fibrin and collagen deposits were evident around intrahepatic bile
ducts in livers of heterozygous control mice fed the ANIT diet. Complete Fbg-deficiency
was associated with elevated serum bile acids, periportal necrosis, and increased
serum ALT activity in mice fed the ANIT diet. Fbg-deficiency was associated
with enhanced hepatic expression of the transcription factor Egr-1 and
enhanced induction of genes encoding the Egr-1-regulated pro-inflammatory
chemokines MCP-1, KC/Gro and MIP-2. Interestingly, peribiliary collagen deposition
was not evident near necrotic areas in Fbg-deficient mice. Taken together, the
results suggest that in this model of chronic cholestasis, fibrin constrains the release
of bile constituents from injured intrahepatic bile ducts, thereby limiting the progression
of hepatic inflammation and hepatocellular injury.
1120 ENDOGENOUS CYP1B1 METABOLISM IN VIVO
CONTROLS ENDOGENOUS LIVER PPAR ACTIVITY
WITHOUT EXPRESSION IN HEPATOCYTES.
J. R. Bushkofsky 1, 2 , M. L. Larsen 3 , S. Wang 3 and C. R. Jefcoate 1, 2, 3 .
1 Endocrinology and Reproductive Physiology, University of Wisconsin-Madison School
of Medicine and Public Health, Madison, WI, 2 Molecular and Environmental
Toxicology Center, University of Wisconsin-Madison, Madison, WI and 3 Department
of Pharmacology, University of Wisconsin-Madison, Madison, WI.
Cytochrome P4501b1 (Cyp1b1) is known as a key mediator in the activation of
PAHs to reactive metabolites that initiate cancer and effect immunosuppression.
Cyp1b1 is highly expressed in multipotential progenitor cells, in endothelia from
various tissues and in macrophage. In endothelia, Cyp1b1 deletion produces increased
oxidative stress, which then disrupts capillary morphogenesis, a model of
angiogenesis. This disruption is reversed by lowering oxygen levels and by addition
of N-acetyl cysteine. Cyp1b1 deletion in mice suppressed diet-induced adiposity,
improved insulin sensitivity and blocked hepatic steatosis caused by high dietary
fat. Although scarcely expressed in hepatocytes, expression of over 2,000 genes was
affected in the liver (p