5-aminolevulinic acid accumulation

There is, however, one lingering concern about such products. Lead is a highly toxic metal. It poisons the enzymes that make hemoglobin. As a result, a hemoglobin precursor called aminolevulinic acid accumulates in the body and causes toxic symptoms ranging from stomach problems to brain abnormalities. The amount of lead in these dyes is very small — less than 1 percent — and studies indicate that our blood absorbs virtually none of it. But does it contaminate the hands of those who apply it And what about the excess lead acetate that winds up in our water supply ... 

Decrease in weight gain moderate liver pathology gross accumulations of hepatic porphyrins and increased delta-aminolevulinic acid synthetase activity Decrease in weight gain comparatively small increase in liver weight... 

Vogiatzis, A.K. and Loumbourdis, N.S. Exposure of Rana ridibunda to lead. I. Study of lead accumulation in various tissues and hepatic k-aminolevulinic acid dehydratase activity, / Appl. Toxicol, 19(l) 25-29, 1999. 

Scheme 4. The heme biosynthetic pathway. In vivo administration of d-aminolevulinic acid induces accumulation of fluorescent protoporphyrin IX (PpIX) preferably in malignant tissues...

Aminolevulinic acid (ALA HCl, Levulan Kerastick) is indicated for the treatment of nonhyperkeratotic actinic keratosis of the face and scalp. It has two components, an alcohol solution vehicle and ALA HCl as a dry solid. The two are mixed prior to application to the skin. When applied to human skin, ALA is metabolized to protoporphyrin, which accumulates and on exposure to visible light produces a photodynamic reaction that generates reactive oxygen species (ROS).The ROS produce cytotoxic effects that may explain therapeutic efficacy. Local burning and stinging of treated areas of skin due to photosensitization can occur. 

Another way of initiation of porphyrin-mediated photod)mamic killing of microorganisms is to use endogenous porphyrins s)mthesized by some bacteria. It was observed that the addition of 5-aminolevulinic acid (ALA)—the precursor on porphyrin bios)mthesis, resulted in the accumulation of sufficient amounts of intracellular porphyrins to initiate the photod)mamic killing of microorganisms upon illumination (Hamblin... 

Aminolevulinic acid, an element in the biosynthesis of heme proteins, may be overexpressed under certain pathological conditions and its accumulation has been correlated with some hepatitic cancers. It is in equilibrium with its enol form and can complex transition-metal ions. In the presence of 02, this may lead to the formation of OH and hence in the presence of DNA to DNA damage which is enhanced in the presence of ferritin (Douki et al. 1998 di Mascio et al. 2000). Superoxide radicals have been assumed to be intermediates in these reactions. Mechanistically, the formation of 02 is certainly very complex, because even in the case of the Fe(II)-EDTA-complex the reduction potential is not low enough to reduce O2 by simple one-electron donation. 

Fig. 2 Examples of photosensitizers presently approved for clinical applications or in clinical studies. mTHPC, tetra (meso-hydroxy) phenyl chlorin BPD-MA, benzoporphyrin derivative Photofrin is a mixture of several compounds where dimers or trimers of the indicated structure are assumed to be of major importance PpIX, protoporphyrin IX - accumulating upon treatment with 5-aminolevulinic acid or its ester derivatives, NPe6, HPPH, Hexyl pyropheophorbide TPPS2a, disulfonated (adjacent) tetraphenylporphin AlPcS2a, disulfonated (adjacent) aluminum phthalocyanine. Areas with ionic side groups are indicated in shadow...

A second major lead-induced toxicity involves interruption of heme synthesis. Lead interacts at several steps in the heme biosynthetic pathway (Figure 21.13). As mentioned above, Pb inhibits the enzyme 8-aminolevulinic acid dehydratase (ALA-D), which catalyzes the second step of heme synthesis involving the condensation of two molecules of aminolevulinic acid (ALA) to form porphobilinogen. The result of this inhibition is the accumulation of aminolevulinic acid in the serum and increased excretion of ALA in the urine. A second major disruption of the heme biosynthetic pathway is Pb inhibition of ferrochelatase. This enzyme is responsible for the incorporation of the ferrous ion (Fe2+) into protoporphrin IX to produce heme (Figure 21.2). Accumulated protoporphrin is incorporated into red blood cells and chelates zinc as the cells circulate. This zinc-protoporphrin complex is fluorescent and used to diagnose Pb poisoning. 

Commercial PCB Mixtures. Urinary coproporphyrin levels were increased in rats that ingested 0.3 or 1.5 mg/kg/day Aroclor 1242 in the diet for 2-6 months (Bruckner et al. 1974). Rats treated with 5 mg/kg/day Aroclor 1254 in the diet had maximum increases in liver microsomal P-450 concentration and liver weight after 1 week, but onset of porphyria and induction of 5-aminolevulinic acid (ALA) synthetase was delayed until 2-7 months of treatment (Goldstein et al. 1974). A marked accumulation of uroporphyrins occurred in the liver, and urinary excretion of coproporphyrin and other porphyrins was increased the largest increase was in uroporphyrins. The uroporphyrins in the liver and urine of the treated rats consisted primarily of 8- and 7-carboxyporphyrins. 

Berg, K., Anholt, H., Bech, O., and Moan, J. (1996) The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolevulinic acid-treated cells, Br. J. Cancer, 74 688-697. 

Hilf, R., Havens, J. J., and Gibson, S.L. (1999) Effect of 8-aminolevulinic acid on protoporphyrin IX accumulation in tumor cells transfected with plasmids containing porphobilinogen deaminase DNA, Photochem. Photobiol., 70 334—340. 

Malik, Z., Kostenich, G., Roitman, L., Ehrenberg, B., and Orenstein, A. (1995) Topical application of 5-aminolevulinic acid, DMSO and EDTA protoporphyrin IX accumulation in skin and tumors of mice, J. Photochem. Photobiol. B Biol., 28 213-218. 

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. 

M.T. Wyss-Desserich, C.H. Sun, P. Wyss, C.S. Kurlawalla, U. Haller, M.W. Bems, Y. Tadir (1996). Accumulation of 5-aminolevulinic acid-induced protoporphyrin IX in normal and neoplastic human endometrial epithelial cells. Biochem. Biophys. Res. Commun., 224, 819-824. 

S. Sassa, S. Schwartz, G. Ruth (1981). Accumulation of protoporphyrin IX from 5-aminolevulinic acid in bovine skin fibroblasts with hereditary erythropoietic protoporphyria. A gene-dosage effect. J. Exp. Med., 153, 1094-1101. 

C. Fritsch, C. Abels, A.E. Goetz, W. Stahl, K. Bolsen, T. Ruzicka, G. Goerz, H. Sies (1997). Porphyrins preferentially accumulate in a melanoma following intravenous injection of 5-aminolevulinic acid. Biol. Chem., 378, 51-57. 

M.R. Stringer, P. Collins, D.J. Robinson, G.I. Stables, R.A. Sheehan-Dare (1996). The accumulation of protoporphyrin IX in plaque psoriasis after topical application of 5-aminolevulinic acid indicates a potential for photodynamic therapy. J. Invest. Dermatol, 107, 76-81. 

In plants treated with these herbicides, damage is light dependent and closely correlated with the level of PPIX that accumulates. PPIX accumulation is apparently largely extraplastidic. Treatment with the porphyrin precursor 5-aminolevulinic acid (ALA), in combination with the heme and chlorophyll pathway inhibitor 2,2 -dypyridyl (DP), results in the accumulation of toxic levels of primarily Mg-PPIX monomethyl ester. DP deregulates porphyrin synthesis and ALA provides additional substrate. DP and other chlorophyll synthesis modulators in combination with ALA can increase the selectivity as well as enhance the efficacy of ALA as a herbicide. Exogenously applied porphyrins are far less effective as herbicides than treatment with compounds that cause plants to accumulate their own porphyrins. 

Soluble lead compoimds exert their toxicity by inhibiting the enzyme necessary for hemoglobin synthesis in blood. This causes 5-aminolevulinic acid (ALA), the precursor of hemoglobin, to accumulate. ALA is responsible for the symptoms of lead poisoning headache, stomach ache, diarrhea, paleness, dysfunctional intestines, kidney malfunction, infertility, miscarriage, and anemia. Lead can inhibit a number of further enzymes because its reacts with thiol groups. It is therefore, a general cell poison. 

There is one case, however, where accumulation of a porphyrin from precursors can be used for therapeutic purposes, namely aminolevulinic acid (ALA) PDT [15,16]. ALA is an endogenous precursor of protoporphyrin IX, which is converted into heme by the cellular machinery. When exogenous ALA is provided to the ceU through topical application, protoporphyrin IX accumulates in high amounts and can be used successfully as a photosensitiser in PDT treatment. ALA PDT is particularly successful in treating of skin tumours and actinic keratoses. 

Inhibition of the enzymes S-aminolevulinic acid dehydrase (5>ALAD), heme synthetase, and ferrochdatase reduces heme syndiesis and causes accumulation of heme precursors (e.g., aminolevulinic acid, coproporphyrins, zinc protoporphyrin) in the blood. 

---