title: 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.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B47 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Miura
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B47 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ito
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B47 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: SBI pharmaceuticals CO., LTD., Izumi Garden Tower 20F, 1-6-1, Roppongi, Minato-ku, Tokyo, 106-6020, Japan.
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: SBI pharmaceuticals CO., LTD., Izumi Garden Tower 20F, 1-6-1, Roppongi, Minato-ku, Tokyo, 106-6020, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B47 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Ogura
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019826:Cholic Acid / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism*; D005641:Tegafur / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011355:Prodrugs; D005641:Tegafur; D006418:Heme; D000622:Aminolevulinic Acid; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D019826:Cholic Acid