Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron

Abstract

Heme oxygenase-1 (HO-1) is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance through affecting the differentiation of dendritic cells. The aim of this study is to determine whether the combination of 5-aminolevulinic acid (ALA) and iron induces HO-1 expression in healthy human peripheral blood mononuclear cells (PBMC). The study was an open labeled, non-randomized, non-placebo-controlled trial using healthy male adults and consisted of three parts. Study A aimed to find the peak HO-1 expression at 0, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration. Study B aimed to examine HO-1 dose dependency at 150, 300, and 600 mg of ALA and the need for iron supplementation. Study C aimed to investigate HO-1 changes during a three-day, repetitive administration of ALA and iron. The combination of ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated with ALA+SFC. Clear dose dependency of ALA+SFC was not detected, and a slight tendency towards a cumulative effect of HO-1 after three-day, repetitive administration was observed. ALA, which is already approved for use in several countries as a diagnosis agent for cancer, has the potential to become a novel therapeutic drug for diseases stemming from unwanted immune response such as autoimmune diseases and the rejection response following organ transplantation.

Dietary 5-aminolevulinic acid enhances adenosine triphosphate production, ecdysis and immune response in Pacific white shrimp, Litopenaeus vannamei (Boone)

“…At 24 hpi (Figure 5e), ALA15 and ALA60 showed increase in HO-1 expression levels, although not significant. Increase in HO-1 gene expression levels after 5-ALA supplementation was reported previously (Nishio et al, 2014;: Ito et al, 2018). To date, the role of HO-1 in shrimp immunity is not known.…”

“…Several studies of vertebrates and vertebrate cell lines support the hypothesis that exogenous 5‐ALA enhances haem synthesis and activity of haemoproteins: 5‐ALA administration (a) increased intracellular haem levels, increasing the activity of cytochrome P450 in vitro (Miura et al., ); (b) increased the activity of cytochrome c oxidase of the electron transport chain and raised ATP levels in mouse liver (Ogura et al., ); (c) enhanced protein expression of mitochondrial complexes III–V in mouse adipose tissue (Ota et al., ); (d) induced REV‐ERBα expression (Yamashita et al., ); and (e) induced both protein and mRNA expression of haem oxygenase‐1 (HO‐1) (a rate‐limiting enzyme in haem degradation) (Nishio et al., : Ito et al., ). 5‐aminolevulinic acid was also reported to enhance the immune response in chickens (Sato et al., ) and pigs (Chen et al., ) and improves growth performance in eels (Yasumoto, Miyanari, Yoshimura, Kondo & Takahashi, ) (although there is some disagreement on the effect of 5‐ALA on growth; see below).…”

“…and (e) induced both protein and mRNA expression of haem oxygenase-1 (HO-1) (a rate-limiting enzyme in haem degradation) (Nishio et al, 2014: Ito et al, 2018. 5-aminolevulinic acid was also reported to enhance the immune response in chickens (Sato et al, 2012) and pigs (Chen et al, 2008) and improves growth performance in eels (Yasumoto, Miyanari, Yoshimura, Kondo & Takahashi, 2012) (although there is some disagreement on the effect of 5-ALA on growth; see below).…”

Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases

“…We previously reported that ALA/SFC enhances HO-1 expression, which has anti-inflammatory and antioxidant activities, in a mouse fatty liver model, and in peripheral blood mononuclear cells of healthy humans 6,8 . We therefore carried out western blot analysis and quantitative reverse transcription PCR of the HO-1 gene.…”

“…We previously reported that ALA supplementation in mice enhances cytochrome c oxidase (COX) activity and ATP production levels in liver, and ALA combined with sodium ferrous citrate (SFC) administration upregulates the expression of OXPHOS complexes III, IV, and V in white adipose tissues of diet-induced obese mice, resulting in reduced lipid content of adipocytes 4,5 . Furthermore, ALA combined with SFC in healthy humans increased the expression levels of haem oxygenase-1 (HO-1) in peripheral blood mononuclear cells, which has cytoprotective effects against oxidative stress and inflammation 6,7 .

Figure 1Haem biosynthesis pathway. Haem is biosynthesised via several steps in the cytoplasm and mitochondria.

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