5-Aminolevulinic Acid (5-ALA): Analysis of Preclinical and Safety Literature

Perez, Michael H.; Rodríguez, Beatriz L.; Shintani, Terry T.; Watanabe, Keitaro; Miyanari, Setsuko; Harrigan, Rosanne C.

doi:10.4236/fns.2013.410131

Cited by 15 publications

(18 citation statements)

References 9 publications

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“…Although an extremely large iron dosage can cause hepatotoxicity as well as gastrointestinal disturbances, a maximum safety level for a repeated dose is indicated as 1,000 mg/kg/day SFC in rats in the generally recognized as safe (GRAS) notice of FDA in the United States, which was then approved as a food ingredient ( 45 ). In addition, the safety of ALA/SFC as a dietary supplement has been reviewed ( 46 ); the safety features of ALA/SFC have also been shown in a study with type II diabetes patients under the therapy with antidiabetes drugs ( 47 ). From the viewpoint of these high levels of safety of ALA/SFC, it is expected that ALA/SFC-based combination therapies with conventional drugs (e.g., ALA/SFC with artemisinin) can be available to reduce the dosage of conventional ones.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

Suzuki

Hikosaka

Balogun

et al. 2015

Antimicrob Agents Chemother

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5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe2+) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug.

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Section: Discussionmentioning

confidence: 99%

In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

Suzuki

Hikosaka

Balogun

et al. 2015

Antimicrob Agents Chemother

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“…Importantly, it was also reported that ALA significantly increased fruit interior quality (Gao et al, 2013; Zhang L. Y. et al, 2015). Furthermore, ALA is readily biodegradable and has no adverse effects on animals and humans (Perez et al, 2013). Therefore, ALA can simultaneously improve fruit coloration and fruit interior quality without any detrimental effects, suggesting great application prospect in fruit production.…”

Section: Introductionmentioning

confidence: 99%

Proteomics and SSH Analyses of ALA-Promoted Fruit Coloration and Evidence for the Involvement of a MADS-Box Gene, MdMADS1

Feng

Zheng

et al. 2016

Front. Plant Sci.

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Skin color is a key quality attribute of fruits and how to improve fruit coloration has long been a major concern. 5-Aminolevulinic acid (ALA), a natural plant growth regulator, can significantly increase anthocyanin accumulation in fruit skin and therefore effectively improve coloration of many fruits, including apple. However, the molecular mechanism how ALA stimulates anthocyanin accumulation in fruit skin remains unknown. Here, we investigated the impact of ALA on apple skin at the protein and mRNA levels. A total of 85 differentially expressed proteins in apple skins between ALA and water treatment (control) were identified by complementary gel-based and gel-free separation techniques. Most of these differentially expressed proteins were up-regulated by ALA. Function analysis suggested that 87.06% of the ALA-responsive proteins were associated with fruit ripening. To further screen ALA-responsive regulators, we constructed a subtracted cDNA library (tester: ALA treatment; driver: control) and obtained 104 differentially expressed unigenes, of which 38 unigenes were indicators for the fruit ripening-related genes. The differentially changed proteins and transcripts did not correspond well at an individual level, but showed similar regulated direction in function at the pathway level. Among the identified fruit ripening-related genes, the expression of MdMADS1, a developmental transcription regulator of fruit ripening, was positively correlated with expression of anthocyanin biosynthetic genes (MdCHS, MdDFR, MdLDOX, and MdUFGT) in apple skin under ALA treatment. Moreover, overexpression of MdMADS1 enhanced anthocyanin content in transformed apple calli, which was further enhanced by ALA. The anthocyanin content in MdMADS1-silenced calli was less than that in the control with ALA treatment, but higher than that without ALA treatment. These results indicated that MdMADS1 is involved in ALA-induced anthocyanin accumulation. In addition, anthocyanin-related verification in apple calli suggested that the regulation of MdMADS1 on anthocyanin biosynthesis was partially independent of fruit ripening process. Taken together, our findings provide insight into the mechanism how ALA regulates anthocyanin accumulation and add new information on transcriptase regulators of fruit coloration.

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“…The oral doses of 5‐ALA chosen in our mouse studies were based on allometric scaling (i.e. by surface area) of the doses typically used (10–60 mg·kg −1 ) for photodynamic therapy and immunofluorescence of tumours in patients (Regula et al ., ; Webber et al ., ; Ackroyd et al ., ; Hinnen et al ., ; Perez et al ., ). As a result, similar concentrations of 5‐ALA would be expected initially in the gastrointestinal tract for both species, being on the order of 10–100 mM.…”

Section: Discussionmentioning

confidence: 97%

The proton‐coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5‐aminolevulinic acid

Xie

Smith

2015

British J Pharmacology

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BACKGROUND AND PURPOSE5-Aminolevulinic acid (5-ALA) has been widely used in photodynamic therapy and immunofluorescence of tumours. In the present study, the intestinal permeability and oral pharmacokinetics of 5-ALA were evaluated to probe the contribution of the proton-coupled oligopeptide transporter 1 (PEPT1) to the oral absorption and systemic exposure of this substrate. EXPERIMENTAL APPROACHIn situ single-pass intestinal perfusions and in vivo oral pharmacokinetic studies were performed in wildtype and Pept1 knockout mice. Perfusion studies were performed as a function of concentration dependence, specificity and permeability of 5-ALA in different intestinal segments. Pharmacokinetic studies were performed after 0.2 and 2.0 μmoL·g À1 doses of 5-ALA. KEY RESULTSThe permeability of 5-ALA was substantial in duodenal, jejunal and ileal regions of wildtype mice, but the residual permeability of 5-ALA in the small intestine from Pept1 knockout mice was only about 10% of that in wildtype animals. The permeability of 5-ALA in jejunum was specific for PEPT1 with no apparent contribution of other transporters, including the proton-coupled amino acid transporter 1 (PAT1). After oral dosing, the systemic exposure of 5-ALA was reduced by about twofold during PEPT1 ablation, and the pharmacokinetics were dose-proportional after the 0.2 and 2.0 μmol·g À1 doses. PEPT1 had a minor effect on the disposition and peripheral tissue distribution of 5-ALA. CONCLUSION AND IMPLICATIONSOur findings suggested a major role of PEPT1 in the intestinal permeability and oral absorption of 5-ALA. In contrast, another proton-coupled transporter, PAT1, appeared to play a limited role, at best.

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5-Aminolevulinic Acid (5-ALA): Analysis of Preclinical and Safety Literature

Cited by 15 publications

References 9 publications

In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

Proteomics and SSH Analyses of ALA-Promoted Fruit Coloration and Evidence for the Involvement of a MADS-Box Gene, MdMADS1

The proton‐coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5‐aminolevulinic acid

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