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

Mai Miura; Kensuke Ito; Maiko Hayashi; Motowo Nakajima; Tohru Tanaka; Shun-ichiro Ogura

doi:10.1371/journal.pone.0131793

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

PLoS One. 2015 Jul 16;10(7):e0131793. doi: 10.1371/journal.pone.0131793. eCollection 2015.

Authors

Mai Miura¹, Kensuke Ito¹, Maiko Hayashi¹, Motowo Nakajima², Tohru Tanaka², Shun-ichiro Ogura¹

Affiliations

¹ Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B47 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
² SBI pharmaceuticals CO., LTD., Izumi Garden Tower 20F, 1-6-1, Roppongi, Minato-ku, Tokyo, 106-6020, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / metabolism
Aminolevulinic Acid / pharmacology*
Cell Line, Tumor
Cholic Acid / pharmacology
Cytochrome P-450 CYP2A6 / genetics
Cytochrome P-450 CYP2A6 / metabolism
Heme / metabolism
Humans
Neoplasm Proteins / metabolism
Prodrugs / metabolism*
Tegafur / metabolism*

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Neoplasm Proteins
Prodrugs
Tegafur
Heme
Aminolevulinic Acid
CYP2A6 protein, human
Cytochrome P-450 CYP2A6
Cholic Acid

Grants and funding

The studies in the authors’ laboratories were supported by the Grant-in-Aid for Scientific Research (C) (No. 26430141) from the Ministry of Education, Culture, Sports, Science and Technology. SBI Pharma CO., LTD., provided support in the form of salaries for authors MN and TT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the author contributions section.