Marie José Vilarem | PubMed Health

PubMed2006

Is nuclear factor kappa-B the missing link between inflammation, cancer and alteration in hepatic drug metabolism in patients with cancer?

In the last few years, several studies have provided a causal link between constitutive activation of nuclear factor kappa-B (NF-kappaB) and the initiation and development of cancer. More recently, it appears that a cancer-induced inflammatory response may be an important factor in the inter-individual variability of the response to and toxic effects of cancer chemotherapy, as well as in the alteration of drug metabolism enzyme expression in patients. The relationships between chronic inflammation (or infection), cancer and drug metabolism are many: chronic infections lead to inflammation, inflammation may lead to cancer, cancer usually leads to an inflammatory syndrome, and inflammation alters the expression of drug metabolising enzymes and thus of the efficiency of cancer chemotherapy. This review focuses on the functional consequences of NF-kappaB activation during oncogenesis and on the expression of the major cytochrome P450s (CYP) involved in anticancer therapies. Finally, the potential role of NF-kappaB as the missing link between inflammation, cancer and alteration in hepatic drug metabolism in patients with cancer is discussed.

Cytochrome P-450 Enzyme System↗

PubMed2003

Pathophysiological factors affecting CAR gene expression.

The body defends itself against potentially harmful compounds, such as drugs and toxic endogenous compounds and their metabolites, by inducing the expression of enzymes and transporters involved in their metabolism and elimination. The orphan nuclear receptor CAR (NR1I3 controls phase I (CYP2B, CYP2C, CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance. Constitutive androstane receptor (CAR) is activated by xenobiotics, such as phenobarbital, but also by toxic endogenous compounds such as bilirubin metabolite(s). To better understand the inter- and intravariability in drug detoxification, we studied the molecular mechanisms involved in CAR gene expression in human hepatocytes. We clearly identified CAR as a glucocorticoid receptor (GR) target gene, and we proposed the hypothesis of a signal transduction where the activation of GR plays a critical function in CAR-mediated cellular response. According to our model, chemicals or pathophysiological factors that affect GR function should decrease CAR function. To test this hypothesis, we recently investigated the effect of microtubule disrupting agents (MIAs) or proinflammatory cytokines. These compounds are well-known inhibitors of GR transactivation property. MIAs activate c-Jun N-terminal kinase (JNK), which phosphorylates and inactivates GR, whereas proinflammatory cytokines, such as IL-6 or IL1beta, induce AP-1 or NF-kB activation, respectively, leading to GR inhibition. As expected, we observed that these molecules inhibit both CAR gene expression and phenobarbital-mediated CYP gene expression in human hepatocytes.

Animals↗