In Vitro Inhibition of Multiple Cytochrome P450 Isoforms by Xanthone Derivatives from Mangosteen Extract

Foti, R.; Pearson, Josh T.; Rock, Dan A.; Wahlstrom, Jan L.; Wienkers, Larry C.

doi:10.1124/dmd.109.028043

Cited by 35 publications

(23 citation statements)

References 31 publications

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“…A previous study in human liver microsomes showing inhibition of P450 by MSBE or mangiferin evidenced direct effects on catalytic activities . Similarly, a comparative study with six xanthone derivatives revealed that these structures produce a non selective in vitro inhibition of multiple P450 enzymes, most of which by a competitive inhibition model (Foti et al, 2009). On the other hand, quantification of the P450 mRNA levels in hepatocytes exposed to MSBE and mangiferin revealed enzyme-specific effects: increases for CYP1A1 and 1A2, reductions for CYP3A4 and 3A5, and no changes for the other analyzed isoforms (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP‐Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes

Rodeiro

Gómez‐Lechón

Pérez

et al. 2012

Phytotherapy Research

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The aqueous stem bark extract of Mangifera indica L. (MSBE) has been reported to have antioxidant, anti-inflammatory and analgesic properties. In previous studies, we showed that MSBE and mangiferin, its main component, lower the activity of some cytochrome P-450 (P450) enzymes in rat hepatocytes and human liver microsomes. In the present study, the effects of MSBE and mangiferin on several P450 enzymes and UDP-glucuronosyltransferases (UGTs) in human-cultured hepatocytes have been examined. After hepatocytes underwent a 48-h treatment with sub-cytotoxic concentrations of the products (50-250 µg/mL), a concentration-dependent decrease of the activity of the five P450 enzymes measured (CYP1A2, 2A6, 2C9, 2D6 and 3A4) was observed. For all the activities, a reduction of at least 50% at the highest concentration (250 µg/mL) was observed. In addition, UGT activities diminished. MSBE considerably reduced UGT1A9 activity (about 60% at 250 µg/mL) and lesser effects on the other UGTs. In contrast, 250 µg/mL mangiferin had greater effects on UGT1A1 and 2B7 than on UGT1A9 (about 55% vs. 35% reduction, respectively). Quantification of specific mRNAs revealed reduced CYP3A4 and 3A5 mRNAs content, and an increase in CYP1A1, CYP1A2, UGT1A1 and UGT1A9 mRNAs. No remarkable effects on the CYP2A6, 2B6, 2C9, 2C19, 2D6 and 2E1 levels were observed. Our results suggest that the activity and/or expression of major P450 and UGT enzymes is modulated by MSBE and that potential herb-drugs interactions could arise after a combined intake of this extract with conventional medicines. Therefore, the potential safety risks of this natural product derived by altering the ADMET properties of co-administered drugs should be examined.

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Section: Discussionmentioning

confidence: 99%

Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP‐Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes

Rodeiro

Gómez‐Lechón

Pérez

et al. 2012

Phytotherapy Research

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“…Of the various processes of carcinogenesis, blocking of tumor initiation through the induction of phase I and II enzymes such as CYP and quinone reductase (QR) is considered as an important cytoprotective mechanism. Xanthones have been reported to induce QR and inhibit P450 activity [46, 47], suggesting that these substances may have potential uses for preventing cancer initiation. Currently, however, there has been limited study regarding the inhibitive effects of xanthones on phase I and II enzymes, and warrant further investigation.…”

Section: Chemopreventive and Chemotherapeutic Potential Of Mangosteenmentioning

confidence: 99%

Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

Shan¹,

Ma²,

Guo³

et al. 2011

CMM

198

119

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Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent.

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“…Mangosteen has been found to be both substrate and inhibitor for multiple hepatic cytochomre P450 isoforms 15. Curcumin accelerates liver injury and liver cellular oedema in mice with injured liver 16.…”

Section: Discussionmentioning

confidence: 99%

Euforia-induced acute hepatitis in a patient with scleroderma

et al. 2012

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Euforia, a supplement containing a variety of natural ingredients, is widely used as an antioxidant and anti-inflammatory formula. It is not approved by the US Food and Drug Administration and its side effects are unknown. We report a 45-year-old woman with limited systemic sclerosis who presented with jaundice and marked elevation of serum transaminases. One month before, she started taking Euforia juice. A liver biopsy disclosed submassive hepatocellular necrosis with histopathological changes consistent with toxic hepatitis. The patient's symptoms resolved with cessation of Euforia. Six months later, she persisted with abnormal liver function tests, but these resolved 18 months after discontinuation of Euforia. The mechanism by which Euforia causes liver injury is unknown. Some ingredients contained in this supplement (green tea, Aloe vera, noni and goji) are linked to hepatic injury. To our knowledge, this is the first report of hepatotoxicity associated with Euforia.

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In Vitro Inhibition of Multiple Cytochrome P450 Isoforms by Xanthone Derivatives from Mangosteen Extract

Cited by 35 publications

References 31 publications

Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP‐Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes

Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP‐Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes

Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

Euforia-induced acute hepatitis in a patient with scleroderma

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