 |
Back
to PCBs and Liver Damage Table of Contents
Vitamins and Minerals May Change
Our Vulnerability to PCB Liver Damage
Study #21
-
dietary selenium deprivation may render the livers of rats
more sensitive to PCB effects
One-month-old male Sprague-Dawley rats maintained for 19
weeks on a low selenium diet with or without supplementation of 2.0 ppm
selenium were injected intraperitoneally with either 500 mg PCB (Aroclor
1254)/kg body weight or placebo 5 days prior to sacrifice. In addition
to aryl hydrocarbon hydroxylase (AHH) activity, PCB treatment also caused
a significant increase in hepatic levels of thiobarbituric acid reactants
(TBAR), reduced glutathione (GSH), GSH-peroxidase, GSH reductase, glucose-6-phosphate
dehydrogenase (G-6-PD), and GSH-S-transferase in rats on the low selenium
diet. The non-selenium-dependent form of GSH peroxidase was mainly responsible
for the increase of hepatic GSH peroxidase upon PCB treatment. Only the
activities of AHH, GSH-S-transferase, and G-6-PD were significantly higher
in the liver of PCB-treated rats fed the selenium-supplemented diet. In
contrast, except for AHH activity, the lung GSH and related enzymes were
not significantly affected by PCB in either of the two dietary groups.
The
results suggest that dietary selenium deprivation renders the livers of
rats more sensitive to PCB effects. (Chow et al, 1981)
Study #22
-
iron greatly sensitizes mice to PCB induced hepatic porphyria
and liver tumor formation
Treatment of Ah-responsive C57BL/10ScSn mice with iron
greatly sensitizes them to induction of hepatic porphyria and tumour formation
by the polychlorinated biphenyl mixture Aroclor 1254. In the present
studies, male C57BL/10ScSn mice received a single dose of iron-dextran
(600 mg Fe/kg) and were fed a diet containing 0.01% Aroclor 1254 for 1,
3 and 5 weeks. By use of HPLC with electrochemical detection, 8-hydroxydeoxyguanosine
(8-OHdG) was then measured in liver DNA as a marker for oxidative damage.
Treatments with iron or Aroclor alone did not result in a significant increase
in 8-OHdG except at 3 weeks following iron treatment. At 1 and 3 weeks
8-OHdG levels were induced approximately 3- and 5-fold above control groups
respectively in iron- and Aroclor-treated animals. Although there was an
apparent 5- to 10-fold increase in the level of 8-OHdG at 5 weeks, this
was partially attributed to the in vitro effects of porphyrins, levels
of which were massively elevated in liver at this time point. The iron/Aroclor-induced
synergistic elevation of 8-OHdG at 1 and 3 weeks was concluded to be due
to in vivo damage, thus suggesting the importance of DNA oxidation in the
early events of carcinogenesis in this system. (Faux et al, 1992)
Study #23
-
PCBs induce liver enzymes (cytochrome P-450), which increases
the oxidative stress caused by iron, which leads to porphyria.
-
PCB-induced uroporphyria may be linked to liver tumors
Possible mechanisms of drug induced uroporphyrias were discussed
with particular reference to the role of iron (7439896) and the possibility
that accelerated uroporphyrinogen (UROgen) oxidation may be important
and serve as an indicator of oxidative stress involving iron. One hypothesis
was that reactive metabolites of polyhalogenated chemicals, formed by cytochrome-P-450
(P450) isozymes, inhibited uroporphyrinogen-decarboxylase (UDC). Increased
porphyria was induced by chlorinated compounds when animals or cells
were pretreated with inducers of P450 isozymes, particularly 3-methylcholanthrene
(MC) (56495) (P448). Hexachlorobenzene (118741) (HCB), 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD) and polyhalogenated biphenyls were known inducers
of P450s. Responsiveness of two mouse strains to porphyria induction by
TCDD correlated with inducibility of P448. HCB and TCDD did not inhibit
UDC directly but an inhibitor could be isolated from treated cells. HCB
could be metabolized to a protein binding reactive product, although this
did not correlate with in-vivo toxicity. This hypothesis did not account
for known synergism of iron nor for porphyria induced by chemically unrelated
compounds. A theory was presented in which chemicals caused chronic induction
of the P450 system, greater production of reduced oxygen metabolites that
mobilized iron, and subsequent direct or indirect inhibition of UDC. Liver
microsomes from MC pretreated chick embryos catalyzed UROgen oxidation
in the presence of NADPH, especially with addition of a uroporphyria
inducing biphenyl. A structure activity relationship was noted for
uroporphyria induction, P448 induction, and microsomal NADPH dependent
UROgen oxidation by two tetrachlorobiphenyls. Increased levels of
reduced oxygen species were produced in liver microsomes from animals treated
with HCB or MC. Iron alone could induce uroporphyria in-vivo and in-vitro,
and there was an apparent association between chemically induced uroporphyria
and liver tumor development. (Smith et al, 1990)
Study #24
-
PCBs and iron together increase the incidence of porphyria
and liver cancer
A study was conducted examining mechanisms underlying the
synergistic effects of iron (7439896) and polychlorinated biphenyl compounds
on the induction of porphyria. The incidence of porphyria and liver cancer
were assessed in mice fed diets containing Aroclor-1254 (11097691) with
or without pretreatment with subcutaneous injections of an iron-dextran
solution. Pretreatment with iron markedly exacerbated the induction of
hepatic porphyria. The porphyria was characterized by decreased hepatic
uroporphyrinogen-decarboxylase and accumulation of uroporphyrin-I and uroporphyrin-III.
Iron pretreatment also potentiated increases in liver weight, the mitotic
rate, oval cell and bile duct proliferation, and cholangiofibrosis in C57BL/10ScSn-mice
compared with aryl hydrocarbon nonresponsive DBA-mice. An accelerated development
of a mononucleated diploid cell population characteristic of many hepatocarcinogenic
regimes in rodents was also identified in C57BL/10ScSn-mice treated with
both iron and Aroclor-1254. Based on these results a possible biochemical
basis for the synergistic effect of iron involving uncoupling of an induced
cytochrome-P450-1A system was described. (Smith et al, 1995)
Study #25
-
PCB-induced cytochrome P450 (particularly the 1A2 isozyme)
plays a key role in uroporphyria
-
ascorbic acid (Vitamin C) prevents this uroporphyria
The purpose of this project is to determine the mechanism
by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related planar
polychlorinated aromatic hydrocarbons such as polychlorinated biphenyls
(PCBs) cause massive liver accumulation of uroporphyrin (URO). This phenomenon
is also seen in human Porphyria Cutanea Tarda (PCT). PCT is usually associated
with alcohol consumption, use of the contraceptive pill, hemodialysis or
diabetes. An additional goal of this project is to determine the relationships
of the uroporphyrias caused by TCDD and other conditions. However most
of the work has centered on that caused by TCDD and related compounds.
Liver cells in tissue culture are used as models for the human and intact
animal conditions. A focus was to find suitable culture models and to determine
the mechanism of the process of URO accumulation. FINDINGS: We have shown
a key role in the uroporphyria of TCDD and PCB-induced cytochrome P450
particularly the 1A2 isozyme. We have shown that the role of the P450
is to catalyze the oxidation of uroporphyrinogen (UROgen). Recently, we
demonstrated that ascorbic acid prevents URO accumulation by the chick
hepatocytes and isolated microsomes. The site of action of the ascorbate
was the first step of the UROgen oxidation and ascorbate was competitive
with UROgen. The mechanism of the oxidation is not completely understood.
Our results suggest that UROgen is a substrate of the P450 and that ascorbate
somehow competes for the oxidizing moiety of the P450. More recently, we
have used a rat strain (ODS) that requires ascorbate in its diet to test
whether normal levels of ascorbate suppress uroporphyria and deficiency
increases uroporphyria. Rats were treated with 3-methylcholanthrene (MC)
and 5-aminolevulinate (ALA) and were maintained on 3 different dietary
levels of ascorbate. We found that low levels of dietary ascorbate (50
and 200 ppm) resulted in a large accumulation of hepatic uroporphyrin in
animals treated with MC plus ALA. At 800 ppm, hepatic uroporphyrin was
quite low, similar to that in normal rats that synthesize their own ascorbate.
The levels of dietary ascorbate did not affect the induction of P450 1A2
that is an essential participant in the uroporphyrin accumulation. These
data suggest that ascorbate has an important role in regulating uroporphyrin
in vivo, and validates results obtained in tissue culture and in vitro
systems for studying the mechanism of the effect of ascorbate. Recent investigations
determined whether iron loading of the ODS rat decreased liver ascorbate.
The effect of iron loading was quite small. We also found that 11/13 of
a group of PCT patients had plasma levels of ascorbate that were clearly
in the deficient range. This was probably due to a poor diet. Smoking,
an inducer of P4501A2, was quite common. The relationship of the TCDD/PCB
caused uroporphyria to the more common human PCT is not yet known. Our
results suggest that the potential role of P4501A2 in this disease needs
to be investigated. Furthermore, our work suggests that ascorbic acid
prevents this condition. In fact our data suggests that PCT is not
more common because UROgen oxidation is prevented in humans by normal levels
of ascorbate. This represents a new and specific role of ascorbate in human
disease. (Sinclair, 1999)
Go to:
|
