title: Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica.
abstract: We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 (CYP) enzymes, whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal (HLM) preparation, the general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol (NBN) and ketoconazole substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic (PK) study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0-48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Suni
authors.initials: S
authors.lastname: Tang
authors.affiliation: Clinical Research Unit, School of Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hale
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lü
mesh_terms: D029969:Angelica / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000378:metabolism*; D002087:Butyrates / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010936:Plant Extracts / Q000378:metabolism*
chemical_list: D001578:Benzopyrans; D002087:Butyrates; D007527:Isoenzymes; D010936:Plant Extracts; D003577:Cytochrome P-450 Enzyme System; C101278:decursin
keywords: Angelica gigas Nakai; Cytochrome P450; Decursin; Decursinol; Decursinol Angelate; Pharmacogenetics