In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes

Bendikov, Matthew Y., Miners, John O., Simpson, Bradley S., Elliot, David J., Semple, Susan J., Claudie, David J., McKinnon, Ross A., Gillam, Elizabeth M. and Sykes, Matthew J. (2016) In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes. Xenobiotica, 1-9. doi:10.1080/00498254.2016.1203041


Author Bendikov, Matthew Y.
Miners, John O.
Simpson, Bradley S.
Elliot, David J.
Semple, Susan J.
Claudie, David J.
McKinnon, Ross A.
Gillam, Elizabeth M.
Sykes, Matthew J.
Title In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes
Journal name Xenobiotica   Check publisher's open access policy
ISSN 1366-5928
0049-8254
Publication date 2016
Year available 2016
Sub-type Article (original research)
DOI 10.1080/00498254.2016.1203041
Open Access Status Not Open Access
Start page 1
End page 9
Total pages 9
Place of publication Abingdon, Oxfordshire United Kingdom
Publisher Taylor & Francis
Collection year 2017
Language eng
Formatted abstract
1. The metabolism of the anti-inflammatory diterpenoid polyandric acid A (PAA), a constituent of the Australian Aboriginal medicinal plant Dodonaea polyandra, and its de-esterified alcohol metabolite, hydrolysed polyandric acid A (PAAH) was studied in vitro using human liver microsomes (HLM) and recombinant UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes.

2. Hydrolysis of PAA to yield PAAH occurred upon incubation with HLM. Further incubations of PAAH with HLM in the presence of UGT and CYP cofactors resulted in significant depletion, with UGT-mediated depletion as the major pathway.

3. Reaction phenotyping utilising selective enzyme inhibitors and recombinant human UGT and CYP enzymes revealed UGT2B7 and UGT1A1, and CYP2C9 and CYP3A4 as the major enzymes involved in the metabolism of PAAH.

4. Analysis of incubations of PAAH with UDP-glucuronic acid-supplemented HLM and recombinant enzymes by UPLC/MS/MS identified three glucuronide metabolites. The metabolites were further characterised by β-glucuronidase and mild alkaline hydrolysis. The acyl glucuronide of PAAH was shown to be the major metabolite.

5. This study demonstrates the in vitro metabolism of PAA and PAAH and represents the first systematic study of the metabolism of an active constituent of an Australian Aboriginal medicinal plant.
Keyword Clerodane diterpenoid
Cytochrome P450
Esterases
Glucuronidation
In vitro–in vivo extrapolation
Polyandric acid A
Reaction phenotyping
UDP-glucuronosyltransferase
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 22 Jul 2016, 09:21:32 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences