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Regioselectivity of human UDP-glucuronosyltransferase isozymes in flavonoid biotransformation by metal complexation and tandem mass spectrometry.

ABSTRACT: Based on reactions with five flavonoids, the regioselectivities of twelve human UDP-glucuronosyltransferase (UGT) isozymes were elucidated. The various flavonoid glucuronides were differentiated based on LC-MS/MS fragmentation patterns of [Co(II)(flavonoid-H)(4,7-diphenyl-1,10-phenanthroline)(2)](+) complexes generated upon post-column complexation. Glucuronide distributions were evaluated to allow a systematic assessment of the regioselectivity of each isozyme. The various UGT enzymes, including eight UGT1A and four UGT2B, displayed a remarkable range of selectivities, both in terms of the positions of glucuronidation and relative reactivity with flavanones versus flavonols.

SUBMITTER: Robotham SA

PROVIDER: S-EPMC3205324 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Regioselectivity of human UDP-glucuronosyltransferase isozymes in flavonoid biotransformation by metal complexation and tandem mass spectrometry.

Robotham Scott A SA Brodbelt Jennifer S JS

Biochemical pharmacology 20110830 11

Based on reactions with five flavonoids, the regioselectivities of twelve human UDP-glucuronosyltransferase (UGT) isozymes were elucidated. The various flavonoid glucuronides were differentiated based on LC-MS/MS fragmentation patterns of [Co(II)(flavonoid-H)(4,7-diphenyl-1,10-phenanthroline)(2)](+) complexes generated upon post-column complexation. Glucuronide distributions were evaluated to allow a systematic assessment of the regioselectivity of each isozyme. The various UGT enzymes, includin ...[more]

PMID: 21889496

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Project description:BackgroundKang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug-drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear.MethodsPK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme.ResultsAfter dosing, 9 alkaloids were found with C max and t 1/2 values of 0.17-422.70 μmol/L and 1.78-4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t 1/2 values of 0.63-7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (f u-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed f u-plasma values of 12.35% and 60.23-87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki no more than 0.1.ConclusionsWe summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.

Project description:Neobavaisoflavone (NBIF), a phenolic compound isolated from Psoralea corylifolia L., possesses several significant biological properties. However, the pharmacokinetic behaviors of NBIF have been characterized as rapid oral absorption, high clearance, and poor oral bioavailability. We found that NBIF underwent massive glucuronidation and oxidation by human liver microsomes (HLM) in this study with the intrinsic clearance (CLint) values of 12.43, 10.04, 2.01, and 6.99??L/min/mg for M2, M3, M4, and M5, respectively. Additionally, the CLint values of G1 and G2 by HLM were 271.90 and 651.38??L/min/mg, respectively, whereas their respective parameters were 59.96 and 949.01??L/min/mg by human intestine microsomes (HIM). Reaction phenotyping results indicated that CYP1A1, 1A2, 2C8, and 2C19 were the main contributors to M4 (34.96??L/min/mg), M3 (29.45??L/min/mg), M3 (13.16??L/min/mg), and M2 (63.42??L/min/mg), respectively. UGT1A1, 1A7, 1A8, and 1A9 mainly catalyzed the formation of G1 (250.87??L/min/mg), G2 (438.15??L/min/mg), G1 (92.68??L/min/mg), and G2 (1073.25??L/min/mg), respectively. Activity correlation analysis assays showed that phenacetin-N-deacetylation was strongly correlated to M3 (r?=?0.860, p?=?0.003) and M4 (r?=?0.775, p?=?0.014) in nine individual HLMs, while significant activity correlations were detected between paclitaxel-6-hydroxylation and M2 (r?=?0.675, p?=?0.046) and M3 (r?=?0.829, p?=?0.006). There was a strong correlation between ?-estradiol-3-O-glucuronide and G1 (r?=?0.822, p?=?0.007) and G2 (r?=?0.689, p?=?0.040), as well as between propofol-O-glucuronidation and G1 (r?=?0.768, p?=?0.016) and G2 (r?=?0.860, p?=?0.003). Moreover, the phase I metabolism and glucuronidation of NBIF revealed marked species differences, and mice are the best animal model for investigating the metabolism of NBIF in humans. Taken together, characterization of NBIF-related metabolic pathways involving in CYP1A1, 1A2, 2C8, 2C19, and UGT1A1, 1A7, 1A8, 1A9 are helpful for understanding the pharmacokinetic behaviors and conducting in-depth pharmacological studies.

Dataset Information

Regioselectivity of human UDP-glucuronosyltransferase isozymes in flavonoid biotransformation by metal complexation and tandem mass spectrometry.

Publications

Regioselectivity of human UDP-glucuronosyltransferase isozymes in flavonoid biotransformation by metal complexation and tandem mass spectrometry.

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