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The marked induction of cytochromes P450 such as CYP1A1 caused by polycyclic aromatic hydrocarbons (PAHs) like 3-methylcholanthrene (MC) is often accompanied by suppression of other hepatic P450s. The molecular mechanisms, functional consequences, and human relevance of P450 down-regulation by PAHs are poorly understood. MC suppresses mRNA levels for CYP2C8, an important human P450, in cultured human hepatocytes. To avoid hepatocyte lot-to-lot variability, we assessed CYP2C8 regulation by MC in HepaRG cells, a terminally differentiated human hepatocellular carcinoma cell line that maintains high P450 expression. MC strongly induced CYP1A1 mRNA levels and markedly down-regulated CYP2C8 mRNA levels in HepaRG cells. Although MC also suppressed CYP2C8 mRNA levels in the HepG2 human hepatocellular carcinoma cell line, basal CYP2C8 expression was extremely low. HepaRG cells appear to be an appropriate model system for studying the mechanisms and functional consequences of CYP2C8 downregulation by PAHs. Key words: cytochrome P450, CYP2C8, drug metabolism, polycyclic aromatic hydrocarbons, 3-methylcholanthrene, HepG2 cells, HepaRG cells, aryl hydrocarbon receptor. Des hydrocarbures polycycliques aromatiques (HPA) comme le 3-methylcholanthrene (MC) induisent fortement des P450 comme le CYP1A1, ce qui est souvent accompagne de l'inhibition d'autres P450. Les mecanismes moleculaires, les consequences fonctionnelles et la pertinence chez l'homme de la regulation a la baisse du P450 par les HPA sont meconnus. Dans les hepatocytes humains en culture, le MC entraine l'abaissement des taux d'ARNm pour le CYP2C8, un important P450 humain. Afin de parer la variabilite entre les hepatocytes d'un lot a l'autre, nous avons evalue la regulation de CYP2C8 par le MC dans des cellules HepaRG, une lignee cellulaire d'hepatome en phase terminale de differentiation, qui maintient l'expression du P450 a des taux eleves. Le MC entrainait une forte induction des taux d'ARNm de CYP1A1 et une regulation a la baisse marquee des taux d'ARNm de CYP2C8 dans les cellules HepaRG. Meme si le MC entrainait aussi un abaissement des taux d'ARNm de CYP2C8 dans la lignee de cellules HepG2 d'hepatome humain, l'expression basale de CYP2C8 etait extremement faible. En somme, les cellules HepaRG semblent constituer un modele approprie pour l'etude des mecanismes et des consequences fonctionnelles de la regulation a la baisse de CYP2C8 qu'entrainent les HPA. [Traduit par la Redaction] Mots-cles : cytochrome P450, CYP2C8, metabolisme des medicaments, hydrocarbures polycycliques aromatiques, 3-methylcholanthrene, cellules HepG2, cellules HepaRG, recepteur des hydrocarbures aryles., Introduction The aryl hydrocarbon receptor (AHR)-mediated induction of drug-metabolizing enzymes such as cytochrome P4501A1 (CYP1A1) is a well-characterized response to polycyclic aromatic hydrocarbon (PAH) exposure. Less understood, in terms of [...]

The purpose of this study was to study the effects of serum folate and plasma pyridoxal 5'-phosphate (PLP) on plasma homocysteine, oxidative stress and antioxidant capacities in 44 hepatocellular carcinoma (HCC) patients and 56 healthy controls. The responses of folate, vitamin B-6, homocysteine, oxidative stress and antioxidant enzyme activities in HCC patients before and after tumor resection were also determined. Patients with HCC before tumor resection had significantly lower folate, PLP, homocysteine, glutathione peroxidase and superoxide dismutase levels, but higher malondialdehyde, total antioxidant capacity and glutathione S-transferase activity when compared with healthy controls. Oxidative stress was significantly decreased to a level similar to that of healthy controls after tumor resection in the HCC group. There were no associations of folate and PLP with plasma homocysteine, indicators of oxidative stress and antioxidant capacities. Serum folate and plasma PLP were not significant factors affecting plasma homocysteine, oxidative stress and antioxidant capacities in patients with HCC. European Journal of Clinical Nutrition (2016) 70, 855-858; doi: 10.1038/ejcn.2015.222; published online 20 January 2016, INTRODUCTION Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Deficient folate and/or vitamin B-6 status might affect normal one-carbon metabolism and thus may increase hepatocellular carcinogenesis through [...]