Cytochrome P450 isoforms in the metabolism of decursin and decursinol angelate from Korean angelica

Jinhui Zhang, Li Li, Suni Tang, Thomas W. Hale, Chengguo Xing, Cheng Jiang, Junxuan Lu

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (2C1917 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C192 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.

Original languageEnglish (US)
Pages (from-to)1211-1230
Number of pages20
JournalAmerican Journal of Chinese Medicine
Volume43
Issue number6
DOIs
StatePublished - Sep 1 2015

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Angelica
Cytochrome P-450 Enzyme System
Protein Isoforms
Genotype
decursin
Pyranocoumarins
Liver
Carboxylic Ester Hydrolases
Alleles
Cytochrome P-450 CYP3A
Ketoconazole
Pharmacogenetics
Esterases

All Science Journal Classification (ASJC) codes

  • Complementary and alternative medicine

Cite this

Zhang, Jinhui ; Li, Li ; Tang, Suni ; Hale, Thomas W. ; Xing, Chengguo ; Jiang, Cheng ; Lu, Junxuan. / Cytochrome P450 isoforms in the metabolism of decursin and decursinol angelate from Korean angelica. In: American Journal of Chinese Medicine. 2015 ; Vol. 43, No. 6. pp. 1211-1230.
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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 (2C1917 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C192 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.",
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Cytochrome P450 isoforms in the metabolism of decursin and decursinol angelate from Korean angelica. / Zhang, Jinhui; Li, Li; Tang, Suni; Hale, Thomas W.; Xing, Chengguo; Jiang, Cheng; Lu, Junxuan.

In: American Journal of Chinese Medicine, Vol. 43, No. 6, 01.09.2015, p. 1211-1230.

Research output: Contribution to journalArticle

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T1 - Cytochrome P450 isoforms in the metabolism of decursin and decursinol angelate from Korean angelica

AU - Zhang, Jinhui

AU - Li, Li

AU - Tang, Suni

AU - Hale, Thomas W.

AU - Xing, Chengguo

AU - Jiang, Cheng

AU - Lu, Junxuan

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AB - 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 (2C1917 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C192 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.

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