Identification of a Tryptanthrin Metabolite in Rat Liver Microsomes by Liquid Chromatography/Electrospray Ionization-Tandem Mass Spectrometry

Lee, Sang Kyu; Kim, Ghee Hwan; Kim, Dong Hyeon; Kim, Dong Hyun; Jahng, Yurngdong; Jeong, Tae Cheon

doi:10.1248/bpb.30.1991

Cited by 19 publications

(12 citation statements)

References 16 publications

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“…SKF-525A (2-diethylaminoethyl-2,2-diphenylvalerate-HCl, proadifen) is a widely used non-specific CYP inhibitor used to investigate the contributions made by CYP-related metabolism (Chung et al ., 2000; Emoto et al ., 2003; Lee et al ., 2007). However, it does not strongly inhibit all CYP family members (Emoto et al ., 2003; Franklin and Hathaway, 2008).…”

Section: Introductionmentioning

confidence: 99%

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

Song

Kwon

et al. 2014

Biomolecules & Therapeutics

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Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2–33.7 μM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.

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Section: Introductionmentioning

confidence: 99%

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

Song

Kwon

et al. 2014

Biomolecules & Therapeutics

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“…Recently, due to its high sensitivity and specificity, LC-MS n has been widely used as a powerful analytical tool for the identification of drug metabolites in biological matrices (Heavner et al, 2005;Hoizey et al, 2006;Li et al, 2006;Lee et al, 2007). It is especially suitable for the analysis of thermolabile, highly polar and non-volatile metabolites.…”

Section: Introductionmentioning

confidence: 99%

Structural elucidation of in vitro metabolites of emodin by liquid chromatography–tandem mass spectrometry

Song

Zhang

et al. 2008

Biomedical Chromatography

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Liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was employed to investigate the in vitro metabolism of emodin. Emodin was incubated with rat liver microsomes in the presence of a NADPH-generating system, followed by extraction with ethyl acetate. After separation on a reversed-phase C18 analytical column with a linear gradient elution of methanol and 0.1% formic acid in water, negative electrospray ionization tandem mass spectrometry experiments were performed. As a result, the parent drug and its six metabolites were detected from rat liver microsomal incubations. The identification of the metabolites and elucidation of their structure were performed by comparing the changes in molecular masses (DeltaM), retention times and MS(2) spectral patterns of metabolites with those of parent drug. Besides three mono-hydroxylated metabolites (omega-hydroxyemodin, 2-hydroxyemodin, 4-hydroxyemodin), three other metabolites were identified, which were emodic acid, 3-carbomethoxy-6-methoxy-1,8-dihydroxyanthraquinone and physcion, respectively.

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“…Spectral data are virtually identical to those reported in the literature [28]. Biotransformation of tryptanthrin Metabolism of tryptanthrin (100 μm, final concentration) was determined with 1 mg/mL of microsomal protein, obtained from rat live using previously reported method [19], in 0.1 m K 2 PO 4 buffer, pH 7.4, at 37°C for 2 h, in a final incubation volume of 500 μL. The reactions were initiated by the addition of an NADPH-generating system containing 0.8 mm NADPH, 10 mm glucose 6-phosphate, and 1 U glucose 6-phosphate dehydrogenase to the reaction mixture.…”

Section: Methodsmentioning

confidence: 64%

“…The MS 2 spectra of protonated tryptanthrin and metabolite (M1) have led us to deduce the position of monohydroxylation as being on the aromatic ring of the indole moiety, and the structure was identified as 8-hydroxytryptanthrin by comparison with a chemically synthesized authentic compound [19]. However, the metabolite (M2) with a mass of 280 has not been characterized as yet.…”

Section: Tryptanthrinmentioning

confidence: 99%

Synthesis of hydroxylated tryptanthrins as possible metabolites and characterization

Kim

Karim

Lü

et al. 2015

Heterocyclic Communications

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A series of dihydroxytryptanthrins was prepared by the reaction of a suitably substituted isatoic anhydride and isatin as possible metabolites of tryptanthrin. A high-performance liquid chromatography analysis of the synthetic compounds confirmed that 8,9-dihydroxytryptanthrin is the metabolite isolated from rat liver cytosolic metabolites. Although tryptanthrin shows strong cytotoxicity against human cancer cell lines, none of the hydroxylated tryptanthrins exhibit any significant cytotoxicity against selected human cancer cell lines up to 50 μm.

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Identification of a Tryptanthrin Metabolite in Rat Liver Microsomes by Liquid Chromatography/Electrospray Ionization-Tandem Mass Spectrometry

Cited by 19 publications

References 16 publications

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

Structural elucidation of in vitro metabolites of emodin by liquid chromatography–tandem mass spectrometry

Synthesis of hydroxylated tryptanthrins as possible metabolites and characterization

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