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Comparison of Metabolism of Sesamin and Episesamin by Drug-Metabolizing Enzymes in Human Liver
Comparison of Metabolism of Sesamin and Episesamin by Drug-Metabolizing Enzymes in Human Liver
- Source :
- Drug Metabolism and Disposition. 40:1917-1926
- Publication Year :
- 2012
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2012.
-
Abstract
- Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.
- Subjects :
- Male
Protein Conformation
Pharmaceutical Science
Dioxoles
Catechol O-Methyltransferase
Lignans
Substrate Specificity
Rats, Sprague-Dawley
chemistry.chemical_compound
Biotransformation
Cytochrome P-450 CYP1A2
Sesamin
Animals
Humans
Enzyme Inhibitors
Glucuronosyltransferase
Cytochrome P-450 CYP2C9
Pharmacology
chemistry.chemical_classification
Molecular Structure
biology
CYP1A2
Cytochrome P450
Metabolism
Recombinant Proteins
Rats
Cytochrome P-450 CYP2C19
Molecular Docking Simulation
Kinetics
Enzyme
Liver
chemistry
Biochemistry
Microsomes, Liver
biology.protein
Microsome
Aryl Hydrocarbon Hydroxylases
Glucuronide
Subjects
Details
- ISSN :
- 1521009X and 00909556
- Volume :
- 40
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism and Disposition
- Accession number :
- edsair.doi.dedup.....51231e2ab4fde47acff7b4a7f7c05c6a
- Full Text :
- https://doi.org/10.1124/dmd.112.045906