Synergism of iron and hexachlorobenzene inhibits hepatic uroporphyrinogen decarboxylase in inbred mice

Smith, Andrew G.; Francis, Jean E.

doi:10.1042/bj2140909

Cited by 94 publications

(71 citation statements)

References 28 publications

(22 reference statements)

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“…We have considered this unlikely, on the basis of data indicating that uroporphyria can be produced in the absence of ALA treatment by combining hexachlorobenzene with Fe dextran or with TCDD alone. 20,43 In addition, no ALA treatment is necessary to cause development of uroporphyria in some mouse strains given Fe dextran alone. 24,41 However, Bechara et al have postulated that metals catalyze the formation of an ALA radical 44 that can release Fe from ferritin in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…These data show that in this new model, URO accumulation is associated with decreases in URO-D, as has been found with other rodent models of uroporphyria. 6,20,21 Hepatic CYP1A2 in Wild-Type, Hfe (؉/؊), and Hfe (؊/؊) Mice.…”

Section: Accumulation Of Hepaticmentioning

confidence: 99%

“…Fe dextran, which has been widely used to enhance hepatic URO accumulation in rodents, 20 caused a 10-fold increase in hepatic Fe. The dose of Fe dextran was 300 mg/kg because the normal mouse dose of 500 mg/kg 27 was lethal to mice of the 129 SvEvTac strain.…”

Section: Accumulation Of Hepaticmentioning

confidence: 99%

“…19 Development of uroporphyria in mice and rats is accelerated by treatment with Fe dextran. 20,21 Furthermore, Fe depletion protects against the uroporphyric effects of dioxin in mice. 22 Uroporphyria can be produced in some inbred mouse strains, by treatment with Fe dextran alone, 23,24 whereas in other inbred strains it requires treatment with Fe dextran plus 5-aminolevulinic acid (ALA), the porphyrin precursor.…”

mentioning

confidence: 99%

“…In C57BL/6 mice in which the Cyp1a2 gene has been knocked out, treatment with ALA and Fe dextran fails to produce uroporphyria, 29 suggesting that an interaction between CYP1A2 and Fe is required in the process. In all cases of experimental uroporphyria, there is inactivation of hepatic URO-D, 6,20,24 and it is thought that Fe has a role in the process, perhaps through oxidative stress. 1,3 In this article, we have studied mice in which the Hfe gene has been disrupted as a model for human hemochromatosis.…”

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confidence: 99%

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Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

et al. 2001

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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 wildtype 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.)

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Section: Discussionmentioning

confidence: 99%

Section: Accumulation Of Hepaticmentioning

confidence: 99%

Section: Accumulation Of Hepaticmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

et al. 2001

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Urinary Porphyrin Excretion in a Human Population Highly Exposed to Hexachlorobenzene

Herrero¹,

Ozalla²,

Sala³

et al. 1999

Arch Dermatol

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Acute effects of orally administered sodium arsenate on heme biosynthetic enzymes in the tissues of three strains of mice

Kondo

Ichikawa

1999

Appl. Organometal. Chem.

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Sodium arsenate (Na2HASO4· 7H2O, As(V)) was administered to three genetically different strains of mice, ICR, C57BL/6J and DBA/2J, in a single oral dose of 54 mg kg−1 body weight. The effects on the activities of heme biosynthetic enzymes in the spleen, liver, kidney and peripheral blood were investigated. The activities of δ‐aminolevulinate synthase (ALAS, EC 2.3.1.37), catalyzing the first reaction in the heme biosynthetic pathway and the rate‐limiting enzyme for heme synthesis, δ‐aminolevuilinate dehydratase (ALAD, EC 4.2.1.24) and porphobilinogen de‐aminase (PBGD, EC 4.3.1.8) in the spleens of the ICR strain, were remarkably reduced to 51%, 32% and 42%, respectively, in comparison with each mean value of the control group. In contrast, these activities were significantly increased in the livers of the C57BL/6J strain, and a similar trend was observed in the DBA/2J strain. In the kidneys, the ALAD activity was significantly reduced in the ICR strain, but no significant differences in the other two strains were found. These results suggest that the influence of As(V) on the activity of heme biosynthetic enzymes is most potently manifested in the spleen tissue of the ICR strain. Copyright© 1999 John Wiley & Sons, Ltd.

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Synergism of iron and hexachlorobenzene inhibits hepatic uroporphyrinogen decarboxylase in inbred mice

Cited by 94 publications

References 28 publications

Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

Urinary Porphyrin Excretion in a Human Population Highly Exposed to Hexachlorobenzene

Acute effects of orally administered sodium arsenate on heme biosynthetic enzymes in the tissues of three strains of mice

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