Hepatic toxicity and uroporphyrinogen decarboxylase activity following a single dose of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin to mice

doi:10.1016/0006-2952(81)90421-4

Biochemical Pharmacology

Volume 30, Issue 20, 15 October 1981, Pages 2825-2830

https://doi.org/10.1016/0006-2952(81)90421-4 Get rights and content

Abstract

A single, low-lethality, oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (75 μg/kg) induces an hepatic porphyria in C57BL/10 mice of either sex. The hepatic porphyrin levels are maximal 4–6 weeks after dosing and are still elevated 12 weeks after the dose. The activity of hepatic uroporphyrinogen decarboxylase is depressed within one week of the dose and this appears to precede the onset of porphyria. Mice of the DBA/2 strain show no changes of the same magnitude at doses of 1200 μg/kg, for porphyrin levels, or 75 μg/kg, for decarboxylase activity. In both strains there is an increase in hepatic iron content 3 weeks after the 75 μg/kg dose. Female C57BL/10 mice are more resistant than males to the lethal effects of TCDD.

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Effect of methapyrilene hydrochloride on hepatic intracellular iron metabolism in vivo and in vitro
2017, Toxicology Letters
Citation Excerpt :
In addition to alterations in the expression of iron-related genes, treatment of rats with 80 mg methapyrilene/kg bw/day resulted in the elevation in the hepatic iron content (Fig. 1B). Interestingly, the similar persistent changes in the expression of the hepatic Tfrc, Tfr2, and Ftl genes and liver iron content have been reported in C57BL/6J mice treated with TCDD (Davies et al., 2008; Smith et al., 1981). The effect of methapyrilene was also assessed in human liver HepaRG cells.
The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with methapyrilene at doses 40 and 80 mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene. A decrease in the level of TF and an increase in the level of FTL also occurred in methapyrilene-treated differentiated HepaRG cells, indicating the existence of interspecies and in vitro-in vivo similarities in the disturbance of cellular iron homeostasis upon liver injury. In contrast, there was minimal overlap in the expression of liver toxicity-marker genes in the livers of rats and in HepaRG cells treated with methapyrilene. Importantly, the decrease of transferrin at mRNA and protein levels occurred after the treatment with a low dose of methapyrilene that exhibited minimal cytotoxicity. These results demonstrate the significance of the dysregulation of hepatic iron metabolism in the pathogenesis and mechanism of chemical-induced liver toxicity and suggest that these changes may be sensitive and useful indicators of potentially hepatotoxic chemicals.
Porphyria Caused by Chlorinated AH Receptor Ligands and Associated Mechanisms of Liver Injury and Cancer
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Chapter 6 Disruption of Heme Synthesis by Polyhalogenated Aromatics
2009, Advances in Molecular Toxicology
Citation Excerpt :
Careful estimations showed that inhibition of UROD appeared before major elevation of hepatic porphyrin levels and liver damage [152]. Such effects are also observed with other polyhalogenated aromatic chemicals [123]. The marked potentiation and prolonged effect of iron on porphyra induced by polychlorinated aromatics led to new avenues of thinking about experimental models of PCT.
The toxic action of aryl hydrocarbon receptor (AHR) ligands appears to be associated with iron metabolism and how this resembles the known human hepatic disorder of heme metabolism, sporadic porphyria cutanea tarda (PCT). Heme is a polycyclicmolecule consisting of an atom of iron at its core in a framework of the tetrapyrrole protoporphyrin IX. It is of immense fundamental importance in biology. The redox nature of the iron and its ability to bind oxygen and molecules such as carbon monoxide and nitric oxide are key to the importance of heme in oxidative respiration, transportation, detection of these gases, and in themany enzymic oxidation reactions that it catalyzes. The disruption of heme synthesis by polyhalogenated aromatic chemicals with physiological consequences has been recognized for decades, which started with the identification of hexachlorobenzene (HCB) as the causative factor of the mass porphyria in Turkey. Both chemical-induced porphyria and sporadic PCT are characterized by accumulation and excretion of uroporphyrins and decreased activity of enzyme uroporphyrinogen decarboxylase (UROD) in the liver. The key part of iron homeostasis in the molecular pathogenesis of both PCT and chemical porphyria would seem to suggest an oxidative mechanism and this is supported by other experimental evidence.
Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
2001, Toxicology and Applied Pharmacology
The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the liver of C57BL/6J mice is a model for clinical sporadic porphyria cutanea tarda (PCT). There is massive uroporphyria, inhibition of uroporphyrinogen decarboxylase (UROD) activity, and hepatocellular damage. A variety of evidence implicates the CYP1A2 enzyme as necessary for mouse uroporphyria. Here we report that, 5 weeks after a single oral dose of TCDD (75 μg/kg), Cyp1a2(+/+) wild-type mice showed severe uroporphyria and greater than 90% decreases in UROD activity; in contrast, despite exposure to this potent agent Cyp1a2(−/−) knockout mice displayed absolutely no increases in hepatic porphyrin levels, even after prior iron overload, and no detectable inhibition of UROD activity. Plasma levels of alanine-aminotransferase (ALT) and aspartate aminotransferase (AST)–although elevated in both genotypes after TCDD exposure–were significantly less in Cyp1a2(−/−) than in Cyp1a2(+/+) mice, suggesting that the absence of CYP1A2 also affords partial protection against TCDD-induced liver toxicity. Histological examination confirmed a decrease in hepatocellular damage in TCDD-treated Cyp1a2(−/−) mice; in particular, there was no bile duct damage or proliferation that in the Cyp1a2(+/+) mice might be caused by uroporphyrin. We conclude that CYP1A2 is both necessary and essential for the potent uroporphyrinogenic effects of TCDD in mice, and that CYP1A2 also plays a role in contributing to TCDD-induced hepatocellular injury. This study has implications for both the toxicity assessment of TCDD and the hepatic injury seen in PCT patients.
Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda
2001, Hepatology
Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/−) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wild-type and Hfe (+/−) mice was mostly in Kupffer cells. In contrast, Hfe (−/−) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (−/−) and Hfe (+/−) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT. (HEPATOLOGY 2001;33:406-412.)
Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
2000, Toxicology
Although in utero maternal stress has been shown to have lasting effects on rodent offspring, fetal effects of chemically-induced alterations of the maternal hypothalamic-pituitary-adrenal axis (HPA) have not been well studied. This study examined the effects of in vivo 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on pituitary-adrenal function in the male rat, pregnant female rat and pregnant female mouse. The secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) in pituitary and adrenal glands, respectively, was assessed in ex vivo perifusion cultures. Male and pregnant female (gestation day 8) Sprague–Dawley rats were gavaged once with 10 μg/kg TCDD, pregnant female mice once with 24 μg/kg TCDD, and euthanized 10 days later. Hemi-pituitary (rat) or whole anterior pituitaries (mice) and right adrenal glands from the same animal were quartered, perifused under baseline and stimulated conditions. In both males and pregnant females, TCDD did not affect corticotropin releasing hormone (CRH)-stimulated ACTH secretion. Neither total pituitary ACTH nor plasma ACTH was altered in either sex or species by TCDD treatment. ACTH-stimulated CORT secretion was not affected by TCDD in either sex or species, and adrenal tissue and plasma CORT levels were unchanged in males and pregnant females by TCDD. However, the plasma ACTH:CORT ratio was decreased about 46% in male rats treated with TCDD. Plasma CORT levels were 23-fold higher and plasma ACTH levels were 1.5-fold higher in pregnant females than in male rats. In male versus female rats, adrenal CORT and anterior pituitary ACTH tissue levels were about 7.5- and 1.75-fold higher and ACTH, respectively. Female mouse adrenal tissue CORT was about 4-fold greater than female rat. The reduced plasma ACTH:CORT ratio in the male rat suggests that TCDD disturbs HPA function. Exposure of male rat to a 5-fold higher dose in earlier studies clearly demonstrated effects of TCDD on male rat HPA. The present study identified substantial HPA performance differences between male and pregnant female rats. The failure to detect a response to TCDD in pregnant female rat and mouse could be a function of both TCDD dose and the high level of secretion of both ACTH and CORT in pregnant animals. For the rat or mouse, a single exposure to TCDD during pregnancy does not appear sufficient to induce maternally-mediated developmental, reproductive and behavioral toxicity via the HPA axis.

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Hepatic toxicity and uroporphyrinogen decarboxylase activity following a single dose of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin to mice

Abstract

Clin. Haemat.

Chem. Biol. Interact.

Toxic. appl. Pharmac.

Food Cosmet. Toxic.

J. biol. Chem.

J. biol. Chem.

Toxic. appl. Pharmac.

Toxic. appl. Pharmac.

J. biol. Chem.

Toxic. appl. Pharmac.

Archs Biochem. Biophys.

J. biol. Chem.

Toxic. appl. Pharmac.

Biochem. Pharmac.

J. biol. Chem.

Human Genet.

Nature, Lond.

Clin. Sci. molec. Med.