Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines.

CYP3A activity is induced by approximately 2-fold during the third trimester of human pregnancy. Placental growth hormone (PGH), estrogens (primarily 17β-estradiol), cortisol, and progesterone have the potential to modulate CYP3A activity. Therefore, we determined whether the elevated plasma concentrations of these hormones during pregnancy induce hepatic CYP3A expression.

An 'all-inclusive' 96-well cytochrome P450 induction method: measuring enzyme activity, mRNA levels, protein levels, and cytotoxicity from one well using cryopreserved human hepatocytes.

Introduction: The traditional in vitro approach for assessing potential CYP induction has been to simply compare changes in CYP activities using known CYP-specific probe substrates following exposure to the test compound to that of vehicle and/or positive controls in primary cultured human hepatocytes. The objective of these current studies was to develop and implement a highly efficient 96-well CYP induction assay in which mRNA levels, protein levels, and the conventional enzyme activities of CYP1A2, CYP2B6, and CYP3A4/5 are all measured in the same well after 48 h. Cytotoxicity is also assessed in the same well after 24 and 48 h of incubation.

Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin.

Background: There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. Recent studies have identified the Frizzled-7 receptor (FZD7), important for activation of Wnt-mediated signaling, as a potential therapeutic target for HCC and other cancers.

Methods: We hypothesized that the extracellular domain of FZD7 (sFZD7) would be a clinically more relevant therapeutic modality than previously studied approaches to target FZD7.

Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery.

The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of critical blood and biliary components. A number of liver-derived in vitro systems, such as slices, primary and immortalized hepatocytes, microsomes and S9 fractions are used to assess the metabolism and potential toxicity of new chemical entities.

Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells.

Background: Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents.

Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo.

Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide. It is intrinsically resistant toward standard chemotherapy, making it imperative to develop novel selective chemotherapeutic agents. The Wnt/beta-catenin pathway plays critical roles in development and oncogenesis, and is dysregulated in HCC.

Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver.

Chenodeoxycholic acid (CDCA) is a liver-formed detergent and plays an important role in the control of cholesterol homeostasis. During cholestasis, toxic bile acids (BA) accumulate in hepatocytes causing damage and consequent impairment of their function. Glucuronidation, a conjugation reaction catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, is considered an important metabolic pathway for hepatic BA.