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.
Highlights
Cytochrome P450 (CYP) is a hemeprotein, virtually present in all organisms, that catalyzes the oxidation of endogenous and xenobiotic lipophilic substrates [1,2]
To evaluate the effect of Aminolevulinic acid (ALA) and sodium ferrous citrate (SFC) on the human gastric cancer cell line MKN28, we determined the levels of the mRNA encoding CYP2A6, which converts tegafur to 5-FU
Because our results suggest that ALA and SFC increased CYP2A6 expression and heme synthesis, we determined whether tegafur was cytotoxic to MKN28 cells in the presense of ALA and SFC
Summary
Cytochrome P450 (CYP) is a hemeprotein, virtually present in all organisms, that catalyzes the oxidation of endogenous and xenobiotic lipophilic substrates [1,2]. We examined the effect of ALA on CYP-dependent anticancer prodrug activation in a human gastric cancer cell line. For this purpose, we focused on the anticancer prodrug tegafur, which is converted to cytotoxic 5-FU by CYP2A6. Our results indicate that the addition of ALA and SFC to cultured cells elevated CYP activity and potentiated prodrug activation, suggesting the potential of ALA for use in CYP-dependent prodrug therapy. This approach might facilitate using lower doses of prodrugs and decrease toxic side effects
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