5-Aminolaevulinic acid

Aminolaevulinic acid hydrochloride [5451-09-2] M 167.6, m 156-158 (dec), pKj 4.05, pKf 8.90 Dried in a vacuum desiccator over P2O5 overnight then crystd by dissolving in cold EtOH and adding dry Et20. 

Other photosensitisers in clinical or pre-clinical trials include zinc phthalocya-nine, aluminium sulphonated phthalocyanines, benzoporphyrins, benzochlorins and purpurin-lS-iV-alkylamides, all of which absorb strongly in the 675-700 nm region. An alternative approach to the photosensitisation in PDT involves the use of 5-aminolaevulinic acid (ALA). This compound itself is not a sensitiser but in human cells it is the key metabolic precursor in the biosynthesis of protoporphyrin IX, which can act as a photosensitiser. Normally the biosynthetic process would continue beyond protoporphyrin IX to the iron containing haem. However, by adding extra ALA and iron chelators, the ferrochelatase action is inhibited and the normal feedback mechanism by-passed resulting in a build up of protoporphyrin IX in the cell. The mechanism is illustrated in Figure 4.24. ... 

Although this may seem straightforward, in some cases, the response is only indirectly related and is therefore not a useful parameter of toxicity to use in a dose-response study. This may apply to situations where enzyme inhibition is a basic parameter but where it may not relate to the overall toxic effect. For example, inhibition by lead of aminolaevulinic acid dehydrase, an enzyme, which is involved in heme synthesis, can be readily demonstrated to be dose related, but is clearly not an appropriate indicator of lead-induced renal toxicity in vivo. 

Reduced synthesis. The synthesis of enzymes may be decreased, resulting in a decrease in the in vivo activity. With cytochrome P-450 there are a number of ways in which this occurs. Thus, administration of the metal cobalt to animals will decrease levels of cytochromes P-450 by inhibiting both the synthesis and increasing the degradation of the enzyme. Thus, cobalt inhibits S-aminolaevulinic acid synthetase, the enzyme involved in heme synthesis. Cobalt will also increase the activity of heme oxygenase, which breaks down the heme portion to biliverdin. The compound 3-amino, 1, 2, 3-triazole decreases cytochromes P-450 levels by inhibiting porphyrin synthesis. 

Lead is widely destributed in the environment, especially in industrial and urban areas, and it is readily absorbed into the mammalian body where it exerts a number of undesirable physiological effects. Its most dramatic action is the inhibition of human red cell 5-aminolaevulinic acid dehydrase activity71), but it also depresses the activities of many enzymes having functionsl -SH groups. Attempts to remove lead from the body using agents such as dimercaptopropanol can result in the formation of lipid-soluble lead complexes that may be carried to the brain and exacerbate the effects of lead poisoning. 

Fang, J.Y., et al. 2004. Enhancement of topical 5-aminolaevulinic acid delivery by erbium YAG laser and microdermabrasion A comparison with iontophoresis and electroporation. Br J Dermatol 151 132. 

Jenkins MR Buonaccorsi GA, Mansfield R, et al, Reduction in the response to coronary and iliac artery injury with photodynamic therapy using 5-aminolaevulinic acid, Cardiovasc Res 2000 45 478-485. 

Gabeler EE, van Hillegersberg R, Statius van Eps RG, et al. Endovascular photodynamic therapy with aminolaevulinic acid prevents balloon induced intimal hyperplasia and constrictive remodelling. Eur J Vase Endovasc Surg 2002 24(4) 322-33 I. 

Biosynthesis of The starting point for heme and chlorophyll synthesis is aminolaevulinic acid... 

Section M Smil, V. (1997) Global population and the nitrogen cycle. Sci. Amer. 277(7), 58-63. Warren, M.J., Cooper, J.B., Wood, S.P. and Shoolingan-Jordan, P.M. (1998) Lead poisoning, haem synthesis and 5-aminolaevulinic acid dehydratase. Trends Biochem. Sci. 23, 217-221. Warren, M.J. and Scott, A.I. (1990) Tetrapyrrole assembly and modification into the ligands of biologically functional cofactors. Trends Biochem. Sci. 15, 486-491. 

The inhibition of chlorophyll biosynthesis by metals was described for higher plants (Bazinsky et al., 1980 Prassad and Prassad, 1987) as well as for algae (De Filippis and Pallaghy, 1976 De Filippis et al., 1981 a). Sensitivity to metals was found for two enzymes of this pathway 8-aminolaevulinic acid (ALA)-dehydratase (EC 4.2.1.24) and protochlorophyllide reductase. Stobart et al. (1985) reported that the synthesis of 8-ALA is also an important site of inhibition in barley (Hordeum vulgare). 

Curnov A,McIlroy BW, Postle-Hacon MJ, Porter JB,MacRobert AJ,Bown SG. Enhancement of 5-aminolaevulinic acid induced photodynamic therapy using hydroxypyridi-none iron chelating agents. Br J Cancer 1998 78 1278. 

During an acute attack, a fresh urine sample which has been protected from light should be sent to a specialist laboratory to be tested for aminolaevulinic acid and porphobilinogen concentrations. If urinalysis confirms raised urinary excretion of aminolaevulinic acid and porphobilinogen, an analysis of faecal porphyrins can be used to identify the specific porphyria. In acute intermittent porphyria faecal porphyrin levels are generally normal. 

However, between attacks urinary levels of aminolaevulinic acid and porphobilinogen may be normal. In this case the demonstration of reduced... 

ALA synthase is a pyridoxal phosphate-dependent enzyme and promotes Schiff-base formation between its coenzyme and glycine (67 in Fig. 37). Nucleophilicity at C-2 of the glycine could be generated either by decarboxylation or by abstraction of a proton. In the first case 5-aminolaevulinic acid would retain both methylene protons of glycine, in the second, one of the protons would be lost to the medium (Fig. 37). Acylation of the pyridoxal-bound intermediate (68 or 69) by succinyl-CoA would constitute the next step and this could be followed either by direct hydrolysis of the Schiff-base or by decarboxylation with subsequent hydrolysis depending on which course was chosen in the first stage of the reaction. 

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. 

Increase in 5-aminolaevulinic acid with decrease in porphyrin decarboxylase... 

Lead Lead poisoning (= saturnism) results in mild, rapidly regressive toxic hepatitis in about 30% of cases. Occasionally, eosinophilic, acid-resistant inclusions are found in the nuclei of the liver cells (so-called lead protein complexes). Steatosis and liver-cell necrosis have also been witnessed. Although there is a correlation between exposure to lead and severity of damage, individual sensitivity to lead can nevertheless vary. In addition, lead intoxication causes an inhibition of erythrocyte 5-aminolaevulinic acid dehydratase and an induction of 5-aminolaevulinic acid synthase. This brings about the manifestation of acute intermittent porphyria. (8)... 

The gene mutation inhibits hydrolytic cleavage of fumarylacetoacetate into fumarate and acetoacetate. Consequently, the toxic precursors maleylacetoacetate and fumarylacetoacetate accumulate in the liver and kidneys. They possess a reactive double bond and can therefore react with macromolecules to assume the properties of alkylating substances. In addition, intracellular glutathione deficiency develops due to the stable complex formation with glutathione, favouring lipid peroxidations. Enhanced formation of 5-aminolaevulinic acid can also be observed during occasional attacks of acute intermittent porphyria (G. Mitchel et al., 1990). 

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