The Effect of 5-Aminolevulinic Acid on Cytochrome P450-Mediated Prodrug Activation

Abstract

Of late, numerous prodrugs are widely used for therapy. The hemeprotein cytochrome P450 (CYP) catalyzes the activation of prodrugs to form active metabolites. Therefore, the activation of CYP function might allow the use of lower doses of prodrugs and decrease toxicity. We hypothesized that the addition of 5-aminolevulinic acid (ALA), a precursor in the porphyrin biosynthetic pathway, enhances the synthesis of heme, leading to the up-regulation of CYP activity. To test this hypothesis, we treated a human gastric cancer cell line with ALA and determined the effect on CYP-dependent prodrug activation. For this purpose, we focused on the anticancer prodrug tegafur, which is converted to its active metabolite 5-fluorouracil (5-FU) mainly by CYP2A6. We show here that ALA increased CYP2A6-dependent tegafur activation, suggesting that ALA elevated CYP activity and potentiated the activation of the prodrug.

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

“…Protoporphyrin IX is used in cancer treatment to identify and destroy tumors by photodynamic diagnosis and therapy . The insertion of ferrous ion into PpIX generates haem in the mitochondria . Additionally, 5‐ALA is known to induce haem oxygenase‐1 (HO‐1) in vitro and in vivo .…”

Accessing the Biocatalytic Potential for C−H‐Activation by Targeted Genome Mining and Screening

“…Minura et al . furthermore showed that the addition of 5 aminolevulinic acid (5‐ALA), a precursor of the porphyrin biosynthesis, led to the up‐regulation of the P450 CYP2A6 activity and prodrug activation . Addition of 5‐ALA in the exponential phase, however, did not show further improvement of the conversion (data not shown).…”

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

“…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).…”

“…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, 2015); (b) increased the activity of cytochrome c oxidase of the electron transport chain and raised ATP levels in mouse liver (Ogura et al, 2011); (c) enhanced protein expression of mitochondrial complexes III-V in mouse adipose tissue (Ota et al, 2017); (d) induced REV-ERBα expression (Yamashita et al, 2014);…”

“…Haem is a prosthetic group that interacts with different apoproteins to form functional haemoproteins (Kumar & Bandyopadhyay, ). Some examples of haemoproteins include catalase and peroxidase, which protect the body against oxidation by hydrogen peroxide (Tsiftsoglou, Tsamadou & Papadopoulou, ); cytochrome P450 family of enzymes, which metabolize drugs and xenobiotics (Gonzalez & Nebert, ; Miura et al., ); respiratory cytochromes of the mitochondrial electron transport chain which is essential for adenosine triphosphate (ATP) production (Möbius et al., ) and REV‐ERBα (Yamashita et al., ) and its insect homologue nuclear receptor E75 (Reinking et al., ), which have roles in circadian rhythms and ecdysis respectively.…”