Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans

Xie, Gang; Zhou, Dingying; Cheng, Ka‐Wing; Wong, Chi Chun; Rigas, Basil

doi:10.1016/j.bcp.2013.01.031

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…CYP2C9, CYP2D6, CYP1A2, and CYP2C19 have already been reported as isoforms capable to catalyze O ‐demethylation reactions . This fact highlight the results obtained because (−)‐grandisin metabolites are formed by demethylation of (−)‐grandisin methoxy groups (Section Metabolite identification and preliminary quantification).…”

Section: Resultsmentioning

confidence: 99%

In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

Barth

Habenschus

Moreira

et al. 2015

Drug Testing and Analysis

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(-)-grandisin is a tetrahydrofuran lignan that displays important biological properties, such as trypanocidal, anti-inflammatory, cytotoxic, and antitumor activities, suggesting its utility as a potential drug candidate. One important step in drug development is metabolic characterization and metabolite identification. To perform a biotransformation study of (-)-grandisin and to determine its kinetic properties in humans, a high performance liquid chromatography (HPLC) method was developed and validated. After HPLC method validation, the kinetic properties of (-)-grandisin were determined. (-)-grandisin metabolism obeyed Michaelis-Menten kinetics. The maximal reaction rate (Vmax ) was 3.96 ± 0.18 µmol/mg protein/h, and the Michaelis-Menten constant (Km ) was 8.23 ± 0.99 μM. In addition, the structures of the metabolites derived from (-)-grandisin were characterized via gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analysis. Four metabolites, 4-O-demethylgrandisin, 3-O-demethylgrandisin, 4,4'-di-O-demethylgrandisin, and a metabolite that may correspond to either 3,4-di-O-demethylgrandisin or 3,5-di-O-demethylgrandisin, were detected. CYP2C9 isoform was the main responsible for the formation of the metabolites. These metabolites have not been previously described, demonstrating the necessity of assessing (-)-grandisin metabolism using human-derived materials.

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Section: Resultsmentioning

confidence: 99%

In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

Barth

Habenschus

Moreira

et al. 2015

Drug Testing and Analysis

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“…Carboxylesterase is another important type of phase I enzyme that metabolizes toxic substances [ 12 , 13 ]. Johnsen et al .…”

Section: Introductionmentioning

confidence: 99%

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

Lin

Chen

et al. 2015

Military Med Res

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BackgroundT-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of one kind of principal phase I drug-metabolizing enzymes (cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.MethodsA chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC- QqQ MS) after a simple pretreatment.ResultsIn the presence of a carboxylesterase inhibitor, only 20 % T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3 % of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.ConclusionCarboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The primary metabolite produced by carboxylesterase is HT-2, and the main metabolite produced by CYP 3A4 is 3′-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.

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“…Of the five major human CYPs, CYP3A4 uniquely hydroxylates PSA to generate four mono-hydroxyl metabolites and two di-hydroxyl metabolites. Similarly, CYP3A4 uniquely catalyzes the hydroxylation of phospho-ibuprofen [10] and phospho-tyrosol-indomethacin [11]. Substrate-binding to CYP3A4 induces a large increase in the volume of its active site [12], likely accounting for its preference for bulky substrates like phospho-compounds.…”

Section: Discussionmentioning

confidence: 99%

“…The partially positively charged sulfur and phosphorus atoms of PSA may interact with the Asp 301 residue of CYP2D6, thereby facilitating its binding and favorable orientation in the active site. As is the case with phospho-tyrosol-indomethacin [11], PSA was hydroxylated and sulfoxidized by CYP3A4 and CYP2D6, respectively. Together, these findings demonstrate not only the important roles of CYP3A4 and 2D6 in the metabolism of phospho-compounds, but also the unique CYP-catalyzed reaction specificity within a given substrate.…”

Section: Discussionmentioning

confidence: 99%

The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

Xie

Cheng

Huang

et al. 2014

Biochemical Pharmacology

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Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked –COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism.

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Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans

Cited by 11 publications

References 27 publications

In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

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