Effect of Oxygen Tension on Hæm and Porphyrin Biosynthesis

Falk, J. E.; Porra, Robert J.; Brown, A. G.; Moss, F. J.; Larminie, Helen E.

doi:10.1038/1841217a0

Cited by 24 publications

(13 citation statements)

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“…The effect on the neoplastic elements of a tumour would possibly differ in different regions depending on how well nourished the cells were. Our data would suggest that such cells would produce more PPIX, but this effect might be counterbalanced if the cells were in a hypoxic region of the tumour, since this may reduce the toxicity of PDT and may also reduce PPIX synthesis (Falk et al, 1959).…”

Section: Discussionmentioning

confidence: 82%

“…It may be influenced by the phase of the cell cycle, the cellular availability of oxygen (Falk et al, 1959) and the pH of the extracellular fluid, which may influence ALA uptake by the cell (Bermudez-Moretti et al, 1993). It has also been demonstrated that certain neoplastic cells have reduced activity of the enzyme ferrochelatase (Shoenfeld et al, 1988;El-Sharabasy et al, 1992).…”

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confidence: 99%

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Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX

Wyld

Burn²,

Reed³

et al. 1997

Br J Cancer

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Summary Photodynamic therapy (PDT) may cause tumour cell destruction by direct toxicity or by inducing cellular hypoxia as a result of microcirculatory shutdown. Aminolaevulinic acid (ALA) causes cellular accumulation of protoporphyrin IX (PPIX) in cells exposed to it in excess. PPIX can be used as a photosensitizer for PDT. Microcirculatory shutdown may be induced by toxicity to the endothelial and vascular smooth muscle (VSM) cells or by release of vasoactive substances. We have studied whether PPIX is produced by endothelial, VSM and tumour cells on exposure to ALA and whether these cell lines are directly damaged by PDT in vitro. Tumour endothelial cells are angiogenic and we have, therefore, investigated the effect of cellular proliferation rates on PPIX generation. Tumour cells generate more PPIX intracellularly than the non-neoplastic cell lines studied and are correspondingly more sensitive to PDT-induced cytotoxicity. Endothelial cells are sensitive to PDT-induced cytotoxicity and accumulate between 1.5 and four times more PPIX when proliferating (as during tumourinduced angiogenesis) than when quiescent. We conclude that PPIX-mediated PDT may exert some of its effects on the microcirculation of treated tissues by direct toxicity to enothelial and VSM cells, and that this toxicity may be enhanced in the tumour microenvironment.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX

Wyld

Burn²,

Reed³

et al. 1997

Br J Cancer

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“…Oxygen may possibly inhibit the action of one or more of the enzymes concerned in bacteriochlorophyll synthesis. Such an affect has been observed with chick red cells where conversion of glycine to porphyrins and haem is inhibited by high tensions of oxygen (Falk, Porra, Brown, Moss & Larminie, 1959). Another possibility is that oxygen acts indirectly by causing the accumulation of a substance which inhibits the action of a key enzyme.…”

Section: Discussionmentioning

confidence: 89%

The Synthesis of Enzymes Concerned in Bacterio-chlorophyll Formation in Growing Cultures of Rhodopseudomonas spheroides

Lascelles

1960

Journal of General Microbiology

132

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SUMMARYThe enzymes 6-aminolaevulic acid synthetase and 6-aminolaevulic acid dehydrase are concerned in the early stages of tetrapyrrole formation; factors controlling their synthesis have been studied in cultures of Rhodopseudornonas spheroides growing exponentially. In organisms growing in the dark under high degrees of aeration the differential rate of synthesis (increase in enzyme/increase in culture density) of both enzymes is about one-third of that in cultures growing anaerobically in the light. Organisms growing in the dark under low degrees of aeration form the enzymes a t rates comparable to those in photosynthetic cultures. Under anaerobic conditions the differential rate of synthesis of both enzymes is decreased by increasing the light intensity. Enzyme synthesis in the light is repressed by oxygen, the effect being overcome on restoration of anaerobic conditions. Formation of bacteriochlorophyll under these various conditions is affected in the same way as enzyme synthesis. Addition of B-aminolaevulic acid or haemin to growing cultures stopped the synthesis of the synthetase and the dehydrase; magnesium protoporphyrin had no such effect. The activity of the synthetase, but not of the dehydrase, was decreased in organisms growing with suboptimal concentrations of biotin. A component of the electron transport chain as well as the intracellular concentration of biosynthetic intermediates may contribute, by mechanisms as yet unknown, to the regulation of synthesis of enzymes involved in bacteriochlorophyll formation.

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“…Specifically, we find that although PpIX production under hypoxic conditions decreases by a factor of 1.4 for low-density exponential cells, it decreases by approximately 20-fold for high-density fed-plateau cells and 42-fold for highdensity unfed-plateau cells. It was shown by Falk et al (1959) that variations in oxygen tension significantly affect the production of haem, protoporphyrin and coproporphyrin in whole blood cells from normal chickens. Recently, Wyld et al (1998) reported that PpIX production by exponentially growing bladder cancer cells was reduced significantly when ALA incubation was performed at 0%, 2.5% and 5% oxygen conditions when compared with that at 21% oxygen.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia significantly reduces aminolaevulinic acid-induced protoporphyrin IX synthesis in EMT6 cells

1999

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SummaryWe have studied the effects of hypoxia on aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) synthesis in EMT6 monolayer cultures characterized by different cell densities and proliferation rates. Specifically, after ALA incubation under hypoxic or normoxic conditions, we detected spectrofluorometrically the PpIX content of the following populations: (a) low-density exponentially growing cells; (b) high-density fed-plateau cells; and (c) high-density unfed-plateau cells. These populations were selected either for the purpose of comparison with other in vitro studies (low-density exponentially growing cells) or as representatives of tumour regions adjacent to (highdensity fed-plateau cells) and further away from (high-density unfed-plateau cells) capillaries. The amount of PpIX per cell produced by each one of these populations was higher after normoxic ALA incubation. The magnitude of the effect of hypoxia on PpIX synthesis was dependent on cell density and proliferation rate. A 42-fold decrease in PpIX fluorescence was observed for the high-density unfed-plateau cells. PpIX production by the low-density exponential cells was affected the least by ALA incubation under hypoxic conditions (1.4-fold decrease), whereas the effect on the high-density fed-plateau population was intermediate (20-fold decrease).

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Effect of Oxygen Tension on Hæm and Porphyrin Biosynthesis

Cited by 24 publications

References 13 publications

Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX

Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX

The Synthesis of Enzymes Concerned in Bacterio-chlorophyll Formation in Growing Cultures of Rhodopseudomonas spheroides

Hypoxia significantly reduces aminolaevulinic acid-induced protoporphyrin IX synthesis in EMT6 cells

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