Porphyrin accumulation

Goldstein, J.A., J.D. McKinney, G.W. Lucier, P. Hickman, H. Bergman, and J.A. Moore. 1976. Toxicological assessment of hexachlorobiphenyl isomers and 2,3,7,8-tetrachlorodibenzofuran in chicks. II. Effects on drug metabolism and porphyrin accumulation. Toxicol. Appl. Pharmacol. 36 81-92. 

Neither vigabatrin nor gabapentin caused porphyrin accumulation in chicken embryo cultured liver cells, whereas felbamate, lamotrigine, and tiagabine were por-phyrinogenic in this model (129). For gabapentin, safety in porphyrias has been confirmed in preliminary clinical observations (SEDA-19, 70) (SEDA-20, 62). 

I 5 Kessel D, Sykes E, Porphyrin accumulation by atheromatous plaques of the aorta, Photochem Photobiol 1984 40(1) 59-61. 

Tsapakos MJ, Hampton TH, Sinclair PR, et al. 1983a. The carcinogen chromate causes DNA damage and inhibits drug-mediated induction of porphyrin accumulation and glucuronidation in chick embryo hepatocytes. Carcinogenesis 4(8) 959-966. 

Huuskonen, S.E., Tuvikene, A., Trapido, M., Fent, K. Hahn, M.E. (2000) Cytochrome P4501A induction and porphyrin accumulation in PLHC-1 fish cells exposed to sediment and oil shale extracts. Archieves of Environmental Contamination and Toxicology 38 59-69. 

Porphyrins Accumulate in Some Inherited Disorders of Porphyrin Metabolism... 

In healthy people, forming haemoglobin for their erythrocytes and haem-dependent enzymes, the rate of haem synthesis is controlled by negative feedback according to the amount of haem present. When more haem is needed there is increased production of the rate-controlling enzyme delta-aminolaevulinic acid (ALA) synthase which provides the basis of the formation of porphyrin precursors of haem. But in people with porphyria one or other of the enzymes that convert the various porphyrins to haem is deficient and so porphyrins accumulate. A vicious cycle occurs less haem —> more ALA synthase —> more porphyrin precursors, the metabolism of which is blocked, and a clinical attack occurs. 

CEP is an autosomal recessive disease. Patients are homoal-lelic or heteroaUelic for mutations in the UROS gene that decrease UROS activity (Table 32-2). Decreased UROS activity leads to massive overproduction of uroporphyrinogen-I and other isomer-I series of porphyrins, mainly in the bone marrow. Porphyrins accumulate in erythrocytes, and their precursors are released into the plasma as these cells die. 

Protection against sunlight and prevention of skin infections are essential. Sunscreen ointments may occasionally provide some benefit, but physical avoidance of UVA radiation is usually necessary. Hypertransfusion and activated charcoal to decrease the enterohepatic circulation of porphyrin, hydroxyurea, intravenous heme, and antioxidant preparations have also been used to suppress erythropoiesis and porphyrin formation or to ameliorate the effects of porphyrin accumulation but none has been shown to have a reliable, long-term effect. Hemolytic anemia may require repeated transfusion and infusion of deferoxamine to prevent iron overload. 

Dermal Exposure. Groups of four New Zealand rabbits were dermally treated with 0 or 42-44 mg/kg/day estimated doses of Aroclor 1260, Clophen A60, or Phenoclor Dpb (all 60% chlorine PCB mixtures), on 5 days/weekfor 28 or 38 days (Vos and Beems 1971 Vos and Notenboom-Ram 1972). The PCBs were dissolved in isopropanol and applied to shaved back skin. All three PCB mixtures caused significantly increased fecal levels of coproporphyrin and protoporphyrin, and ultraviolet fluorescence, indicative of porphyrin accumulation, was increased in the liver and other tissues. Similar dermal exposure to the congener PCB 153 caused higher fecal levels of coproporphyrin and protoporphyrin than those in rabbits exposed to the same dose of Aroclor 1260 (Vos and Notenboom-Ram 1972). 

Tunstall, R.G., Barnett, A.A., Schofield, J., Griffiths, J., Vernon, D.I., Brown, S.B., and Roberts, D.J. (2002) Porphyrin accumulation induced by 5-aminolevulinic acid esters in tumor cells growing in vitro and in vivo, Br. J. Cancer, 87 246-250. 

We devised a screen for isolating mutants defective in iron-dependent regulation of heme biosynthesis that did not require prior knowledge of the mechanism or of the rate-limiting steps [83]. We speculated that if the pathway as a whole were regulated by iron, a mutant defective in that control would accumulate protoporphyrin under iron limitation. Mutants defective in the heme synthesis enzymes ferrochelatase [75] or protoporphyrinogen oxidase would likely have a similar phenotype, but porphyrin accumulation would likely be independent of iron in the structural gene mutants, and those strains would also be expected to be heme auxotrophs. 

The basic concept upon which ALA-PDT is based was conceived as we studied the biochemical basis for the group of metabolic diseases known as the porphyrias [43]. Some of the porphyrias are associated with a generalized photosensitization which is caused by the accumulation of specific types of porphyrin in the blood and/or tissues, where each type of porphyrin accumulates as the result of a specific abnormality in the biosynthetic pathway for heme. Although at that time it was generally believed that the expression of such abnormalities was restricted to the liver and the hemopoietic system (those tissues which synthesize large amounts of heme), it was obvious that all nucleated cells must have at least some capacity to synthesize heme because they all use heme-containing enzymes for the tricarboxylic acid cycle. 

Optimum porphyrin accumulation in epithelial skin tumors and psoriatic lesions after topical application of (5-aminolaevulinic acid. Br. J. Cancer, 79, 1603-1608. 

C. Fritsch, P. Lehmann, W. Stahl, K.W. Schulte, E. Blohm, K. Lang, H. Sies, T. Ruzicka (1999). Optimum porphyrin accumulation in epithelial skin tumors and psoriatic lesions after topical application of delta-aminolaevulinic acid (Review). Br. J. Cancer, 79(9-10), 1603-1608. 

Two approaches to stimulation of porphyrin accumulation in plants have been taken. The first is to supply the plant with the porphyrin precursor 5-aminolevulinc acid (ALA) along with compounds that affect the porphyrin pathway. The second is to block porphyrin synthesis at the protoporphyrinogen oxidase step in the pathway, thereby deregulating the pathway and causing accumulation primarily of PPIX. 

ALA plus DP acted synergistically as herbicides, despite the fact that there was generally only an additive effect on total porphyrin accumulation (Table I). These results indicate one or more of the following (a) one of the earlier chlorophyll intermediates (MgPPIXME or PPIX) is more herbicidal than PChlide,... 

---