Porphyrin-heme biosynthesis in organotypic cultures of mouse dorsal root ganglia. Effects of heme and lead on porphyrin synthesis and peripheral myelin.

Whetsell, William O.; Sassa, Shigeru; Kappas, Attallah

doi:10.1172/jci111457

Cited by 22 publications

(22 citation statements)

References 25 publications

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“…No fluorescence was visible in the demyelinated axons; however, silverimpregnation staining after fixation demonstrated continuity of the axon despite the severe loss of myelin. When cultures were continuously incubated with lead acetate and heme together for 6 weeks, the segmental demyelination seen in cultures treated with lead alone did not occur (Whetsell et al, 1984).…”

Section: Downloaded By [Rmit University] At 22:30 14 August 2015mentioning

confidence: 96%

“…Well-myelinated cultures of mouse dorsal root ganglia incubated for 48 h with 6-ALA showed intense porphyrin fluorescence localized in myelin sheaths but not in axons or neuronal somata (Whetsell et al, 1984). When the cultures were continuously incubated with a high concentration of lead acetate, focal swellings and segmental degeneration of myelin began to develop within 2 weeks, from the nodes of Ranvier, such that the nodes became increasingly wide.…”

Section: Downloaded By [Rmit University] At 22:30 14 August 2015mentioning

confidence: 97%

“…The fact that chronic lead exposure produces damage to the Schwann cells (Lampert and Schochet, 1968;Ohnishi et al, 1977;Schlaepfer, 1969), the demonstration that lead impairs the integrity of the heme biosynthetic pathway (Buchet et al, 1976;Chisolm et al, 1975;Gibson and Goldberg, 1970;Granick et al, 1973;Sassa, 1978;Sassa et al, 1973), and the primary localization of the pathway in the supporting elements of dorsal root ganglia (Sassa et al, 1979b;Whetsell et al, 1978Whetsell et al, , 1979 have led Whetsell et al (1984) to study the possible relationship between lead-induced demyelination and impaired porphyrin heme biosynthesis in the model system. Their results support the idea that there is a relationship between leadinduced imipairment of porphyrinogenesis in cultured dorsal root ganglia cells and the demyelinating process produced as a consequence of sustained exposure of such cells to this metal.…”

Section: Heme and Lead Toxicity On Porphyrin Synthesis And Periphmentioning

confidence: 99%

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Chemistry and Biology of Heme Effect of Metal Salts, Organometals, and Metalloporphyrins on Heme Synthesis and Catabolism, with Special Reference to Clinical Implications and Interactions with Cytochrome P-450

Beri

Chandra

1993

Drug Metabolism Reviews

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Although free porphyrins occur in nature in small quantities, no known function has been assigned to them. In contrast, heme and cobalamin, which are Fe and Co chelates of porphyrins or porphyrin derivatives, respectively, carry out crucial biological functions. Heme is the prosthetic group for a number of hemoproteins. These include myoglobin and hemoglobin, which carry out oxygen binding or transport; mitochondrial cytochromes aa3, b, c, and c3, which are important in transferring electrons; microsomal cytochrome P-450, which catalyzes mixed-function oxidations; catalase, which decomposes H2O2; peroxidase, which activates H2O2; and tryptophan pyrrolase, which catalyzes the oxidation of tryptophan. Recently, heme has also been shown to be the prosthetic group of prostaglandin and peroxide synthetase and indoleamine dioxygenase. The elegant studies of the biochemical pathway for the formation of heme demonstrated the arrangement in the porphyrin macrocycle of the carbon and nitrogen atoms originating from the eight glycine and the succinic acid molecule that are the precursors of porphyrins. There are eight enzymes involved in the synthesis of heme. The first and last three of these enzymes are localized in mitochondria, while the intermediate enzymes are localized in cytosol. The catalytic site of HMOX recognizes metalloporphyrins with central metal atoms other than iron; it favors some of these metalloporphyrins over heme as a potential substrate, sometimes by a large factor, permitting the synthetic heme analogue to serve as a potent competitive inhibitor of HMOX reaction. Since these synthetic metalloporphyrins do not bind molecular oxygen, they are not metabolically degraded by ring rupture and do not add to the body pool of bile pigment. One possible consequence of this competitive inhibition of heme degradation is suppression of bile pigment formation to such a degree that excessive plasma levels of bilirubin may be diminished. The studies of Drummond and Kappas (1981) and later studies in rats, mice, monkeys, and man, and also our studies have proved the latter phenomenon. The compound does not appear to affect the metabolic disposition of preformed bilirubin but inhibits biliary bilirubin excretion derived from the metabolism of endogenous or exogenous heme. Whether some of the effect of Sn-PP on naturally occurring or experimentally induced jaundice in animals reflects diversion of heme to nonheme to oxygenase-dependent pathways of heme metabolism, or whether a pathway which is normally latent becomes activated concurrent with HMOX inhibition is not known.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Downloaded By [Rmit University] At 22:30 14 August 2015mentioning

confidence: 96%

Section: Downloaded By [Rmit University] At 22:30 14 August 2015mentioning

confidence: 97%

Section: Heme and Lead Toxicity On Porphyrin Synthesis And Periphmentioning

confidence: 99%

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Chemistry and Biology of Heme Effect of Metal Salts, Organometals, and Metalloporphyrins on Heme Synthesis and Catabolism, with Special Reference to Clinical Implications and Interactions with Cytochrome P-450

Beri

Chandra

1993

Drug Metabolism Reviews

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“…Heme has been essentially innocuous when administered in pharmacological doses for therapeutic purposes in patients with neurological exacerbations of the genetic liver disease, acute intermittent porphyria (13,14). Moreover, in contrast to the recognized neurotoxicity of bilirubin, heme is known to stimulate neurite growth in cultured neuroblastoma cells (15) and, recently, high concentrations of heme were found to protect against the toxic demyelinating action of lead in a cultured peripheral neuronal cell system (16). Nevertheless, it would be useful to have information on the possible cellular accumulation or the metabolic disposition of heme in the whole animal after Sn-protoporphyrin administration.…”

mentioning

confidence: 99%

The liver excretes large amounts of heme into bile when heme oxygenase is inhibited competitively by Sn-protoporphyrin.

Kappas

Simionatto

Drummond

et al. 1985

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

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“…Heme also has neurotrophic properties in brain tissue. Heme protects mouse dorsal root ganglion cultures from segmental demyelination caused by lead (Whetsell et al, 1984). More pertinent to AD perhaps, heme had growth promoting effects in mouse neuroblastoma cells, and neurites were rapidly lost when heme was removed from culture medium (Ishii and Maniatis, 1978).…”

Section: Neuritic Pathology and The Ferric Cyclementioning

confidence: 99%

Ferric Cycle Activity and Alzheimer Disease

Dwyer¹,

Takeda²,

Zhu³

et al. 2005

CNR

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Elevated plasma homocysteine is an independent risk factor for the development of Alzheimer disease, however, the precise mechanisms underlying this are unclear. In this article, we expound on a novel hypothesis depicting the involvement of homocysteine in a vicious circle involving iron dysregulation and oxidative stress designated as the ferric cycle (Dwyer et al., 2004). Moreover, we suspect that the development of a critical heme deficiency in vulnerable neurons is an additional consequence of ferric cycle activity. Oxidative stress and heme deficiency are consistent with many pathological changes found in Alzheimer disease including mitochondrial abnormalities and impaired energy metabolism, cell cycle and cell signaling abnormalities, neuritic pathology, and other features of the disease involving alterations in iron homeostasis such as the abnormal expression of heme oxygenase-1 and iron response protein 2. Based on the ferric cycle concept, we have developed a model of Alzheimer disease development and progression, which offers an explanation for why sporadic Alzheimer disease is different than normal aging and why familial Alzheimer disease and sporadic Alzheimer disease could have different etiologies but a common end-stage.

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Porphyrin-heme biosynthesis in organotypic cultures of mouse dorsal root ganglia. Effects of heme and lead on porphyrin synthesis and peripheral myelin.

Cited by 22 publications

References 25 publications

Chemistry and Biology of Heme Effect of Metal Salts, Organometals, and Metalloporphyrins on Heme Synthesis and Catabolism, with Special Reference to Clinical Implications and Interactions with Cytochrome P-450

Chemistry and Biology of Heme Effect of Metal Salts, Organometals, and Metalloporphyrins on Heme Synthesis and Catabolism, with Special Reference to Clinical Implications and Interactions with Cytochrome P-450

The liver excretes large amounts of heme into bile when heme oxygenase is inhibited competitively by Sn-protoporphyrin.

Ferric Cycle Activity and Alzheimer Disease

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