Uroporphyria produced in mice by 20-methylcholanthrene and 5-aminolaevulinic acid

Urquhart, Andy; Elder, George H.; Roberts, Andrew; Lambrecht, Richard W.; Sinclair, Peter R.; Bement, William J.; Gorman, Nadia; Sinclair, J.A.

doi:10.1042/bj2530357

Cited by 44 publications

(30 citation statements)

References 45 publications

(46 reference statements)

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“…We, and others, have generated mouse models of S-PCT by administering iron and inducers of the aryl-hydrocarbon receptor battery of cytochrome P450s (8)(9)(10)(11)(12)(13). Early reports indicated the presence of an inhibitor of URO-D activity in heat-denatured liver cytosols from porphyric animals (14-16), a finding we confirmed (13).…”

supporting

confidence: 60%

A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda

Phillips¹,

Bergonia²,

Reilly

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

102

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Porphyria cutanea tarda (PCT), the most common form of porphyria in humans, is due to reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Previous studies have demonstrated that protein levels of URO-D do not change when catalytic activity is reduced, suggesting that an inhibitor of URO-D is generated in hepatocytes. Here, we describe the identification and characterization of an inhibitor of URO-D in liver cytosolic extracts from two murine models of PCT: wild-type mice treated with iron, ␦-aminolevulinic acid, and polychlorinated biphenyls; and mice with one null allele of Uro-d and two null alleles of the hemochromatosis gene (Uro-d ؉/؊ , Hfe ؊/؊ ) that develop PCT with no treatments. In both models, we identified an inhibitor of recombinant human URO-D (rhURO-D). The inhibitor was characterized by solid-phase extraction, chromatography, UV-visible spectroscopy, and mass spectroscopy and proved to be uroporphomethene, a compound in which one bridge carbon in the uroporphyrinogen macrocycle is oxidized. We synthesized uroporphomethene by photooxidation of enzymatically generated uroporphyrinogen I or III. Both uroporphomethenes inhibited rhURO-D, but the III isomer porphomethene was a more potent inhibitor. Finally, we detected an inhibitor of rhURO-D in cytosolic extracts of liver biopsy samples of patients with PCT. These studies define the mechanism underlying clinical expression of the PCT phenotype, namely oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of URO-D. The oxidation reaction is iron-dependent.heme ͉ porphyrins ͉ iron ͉ oxidation

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supporting

confidence: 60%

A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda

Phillips¹,

Bergonia²,

Reilly

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

102

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“…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%

“…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.…”

mentioning

confidence: 99%

“…1 The disease is associated with intake of alcoholic beverages or estrogenic steroids, with hepatitis C virus infection and with excess hepatic iron (Fe). [1][2][3][4][5] Data from experimental animals suggest that uroporphyrinogen oxidation, catalyzed by CYP1A2, leads to inhibition of hepatic URO-D, 2,6,7 but it is not clear if this is the mechanism of URO-D inactivation in the human disease.…”

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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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“…Whether this putative UROD inhibitor causes UROD inactivation in vivo has yet to be determined. There is evidence that UROD inhibition results from the increased uroporphyrinogen accumulating when porphyrin synthesis is stimulated by administration of ALA. 40 With the development of a model for alcoholinduced uroporphyria, whether the inhibitor is formed in this uroporphyria can now be examined.…”

Section: Discussionmentioning

confidence: 99%

Uroporphyria caused by ethanol in Hfe(−/−) mice as a model for porphyria cutanea tarda

et al. 2003

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Two major risk factors for the development of porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). To develop an animal model, Hfe knockout mice were treated continuously with 10% ethanol in drinking water. By 4 months, uroporphyrin (URO) was detected in the urine. At 6 to 7 months, hepatic URO was increased and hepatic uroporphyrinogen decarboxylase (UROD) activity was decreased. Untreated Hfe(؊/؊) mice or wild-type mice treated with or without ethanol did not show any of these biochemical changes. Treatment with ethanol increased hepatic nonheme iron and hepatic 5-aminolevulinate synthase activity in Hfe(؊/؊) but not wild-type mice. The increases in nonheme iron in Hfe(؊/؊) mice were associated with diffuse increases in iron staining of parenchymal cells but without evidence of significant liver injury. In conclusion, the results of this study suggest that the uroporphyrinogenic effect of ethanol is mediated by its effects on hepatic iron metabolism. Ethanol-treated Hfe(؊/؊) mice seem to be an excellent model for studies of alcohol-mediated PCT. (HEPATOLOGY 2003;37:351-358.)

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Uroporphyria produced in mice by 20-methylcholanthrene and 5-aminolaevulinic acid

Cited by 44 publications

References 45 publications

A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda

A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda

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

Uroporphyria caused by ethanol in Hfe(−/−) mice as a model for porphyria cutanea tarda

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