Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
AIM: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. METHODS: Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. RESULTS: In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). CONCLUSIONS: In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.
ISSN: 0269-2813

hal-00702125
https://hal.archives-ouvertes.fr/hal-00702125
DOI : 10.1111/j.1365-2036.2006.03116.x
PUBMED : 17014579

Éditeur(s) : HAL CCSD American Society for Pharmacology and Experimental Therapeutics (ASPET)
Résumé : International audience
Most human hepatocyte cell lines lack a substantial set of liver-specific functions, especially major cytochrome P450 (P450)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the HepaRG cells, derived from a human hepatocellular carcinoma, which exhibit a high differentiation pattern after 2 weeks at confluency to determine whether they could mimic human hepatocytes for drug metabolism and toxicity studies. We show that when passaged at low density, these cells reversed to an undifferentiated morphology, actively divided, and, after having reached confluency, formed typical hepatocyte-like colonies surrounded by biliary epithelial-like cells. By contrast, when seeded at high density, hepatocyte-like clusters retained their typical differentiated morphology. Transcripts of various nuclear receptors (aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor alpha), P450s (CYP1A2, 2C9, 2D6, 2E1, 3A4), phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1), and other liver-specific functions were estimated by reverse transcriptase-quantitative polymerase chain reaction and were found to be expressed, for most of them, at comparable levels in both confluent differentiated and high-density differentiated HepaRG cells and in cultured primary human hepatocytes. For several transcripts, the levels were strongly increased in the presence of 2% dimethyl sulfoxide. Measurement of basal activities of several P450s and their response to prototypical inducers as well as analysis of metabolic profiles and cytotoxicity of several compounds confirmed the functional resemblance of HepaRG cells to primary cultured human hepatocytes. In conclusion, HepaRG cells constitute the first human hepatoma cell line expressing high levels of the major P450s involved in xenobiotic metabolism and represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.
ISSN: 0090-9556

hal-00702085
https://hal.archives-ouvertes.fr/hal-00702085
DOI : 10.1124/dmd.105.006759
PUBMED : 16204462

Éditeur(s) : HAL CCSD Cancer Research UK
Résumé : International audience
BACKGROUND: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. METHODS: Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. RESULTS: Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. CONCLUSION: These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
ISSN: 0007-0920

hal-00684528
https://hal.archives-ouvertes.fr/hal-00684528
DOI : 10.1038/bjc.2012.6
PUBMED : 22294184