Mangifera indica L. extract and mangiferin modulate cytochrome P450 and UDP-glucuronosyltransferase enzymes in primary cultures of human hepatocytes.

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.

Steatotic liver: a suitable source for the isolation of hepatic progenitor cells.

BACKGROUND: Alternative and/or complementary sources of cells such as hepatic progenitor cells (HPC) are under investigation for hepatic cell therapy purposes. Steatotic livers are those most commonly rejected for clinical transplantation and are also unsuitable for good quality hepatocyte isolation. AIM: Taken together these two facts, our aim was to investigate whether they could represent a suitable source for the isolation of progenitor cells. METHODS: Rats fed for 7 weeks with methionine-choline deficient diets showing proved steatotic signs (i.e. increase in hepatic lipids; macrovesicular steatosis) and steatotic and normal human liver samples were used to study the expression of HPC markers and to isolate these cells. RESULTS: In the liver of the steatotic rats there was a significant increase in HPC (known as oval cells in rodents) markers such as Thy-1, epithelial cell adhesion molecule (EpCAM) and OV-6 (2-, 3- and 5-fold increase respectively). Additionally, there was an increase in the yield of isolated oval cells compared to control rats. Similarly, studies using human livers clearly confirmed an increase in the expression of HPC markers in the steatotic tissue and a significant rise in the number of isolated progenitor cells (EpCAM+, Thy-1+, OV-6+) (10, 12 and 11.6 × 10(4)  cells/g of tissue respectively). CONCLUSIONS: These data suggest that steatotic livers, discarded for orthotopic liver transplantation and hepatocyte isolation, could be a suitable source for large scale isolation of HPC which might be potential candidates in liver cell therapy.