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      The effects of single nucleotide polymorphisms in CYP2A13 on metabolism of 5-methoxypsoralen.

      Drug metabolism and disposition: the biological fate of chemicals
      Aryl Hydrocarbon Hydroxylases, genetics, physiology, Escherichia coli, Humans, Methoxsalen, analogs & derivatives, metabolism, Polymorphism, Single Nucleotide, Recombinant Proteins

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          Abstract

          A number of studies have demonstrated that cytochrome P450 (P450) converts furanocoumarin derivatives into reactive molecules, which form covalent bonds to biomolecules. 5-Methoxypsoralen (5-MOP) is a natural furanocoumarin from apiaceous plants. In this study, we examined the effect on 5-MOP metabolism of single nucleotide polymorphisms (SNPs) in CYP2A13. We used Escherichia coli-generated recombinant enzymes of wild-type CYP2A13*1 and five variants, CYP2A13*4 (R101Q), CYP2A13*5 (F453Y), CYP2A13*6 (R494C), CYP2A13*8 (D158E), and CYP2A13*9 (V323L). In high-performance liquid chromatography analyses of 5-MOP metabolic products, CYP2A13*1 converted 5-MOP into 5-MOP dihydrodiol; K(m) and V(max) values of the reaction were 1.44 ± 0.17 μM and 4.23 ± 0.36 nmol/(min · nmol P450), respectively. The generation of a dihydrodiol from 5-MOP implies that conversion by CYP2A13 causes toxicity due to the formation of covalent bonds with DNA or proteins. Most of the CYP2A13 variants could metabolize 5-MOP; K(m) values for CYP2A13*5, *6, *8, and *9 were 1.63 ± 0.12, 1.36 ± 0.10, 0.85 ± 0.09, and 0.58 ± 0.06 μM, respectively, and V(max) values were 3.20 ± 0.13, 4.69 ± 0.13, 2.34 ± 0.07, and 1.84 ± 0.09 nmol/(min · nmol P450), respectively. However, the processing of 5-MOP by CYP2A13*4 was not detectable. Based on this data, we hypothesize that SNPs within the CYP2A13 gene affect metabolism of 5-MOP in humans.

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