Biomedical subjects

Catherine Stedman

Publications and source records attributed to Catherine Stedman.

3 recordsLinked to original sources

PubMed2006

Benefit of farnesoid X receptor inhibition in obstructive cholestasis.

The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.

Animals↗

PubMed2003

Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice.

Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6beta-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

Animals↗

PubMed2002

Herbal hepatotoxicity.

Herbal hepatotoxicity is increasingly recognized as herbal medicines become more popular in industrialized societies. Some herbal products may potentially benefit people with liver disease; however, these benefits remain generally unproved in humans, and a greater awareness of potential adverse effects is required. Herbal use is often not disclosed, and this may result in a diagnostic delay and perpetuation or exacerbation of liver injury. Female gender may predispose to hepatotoxicity, and concomitant agents that induce cytochrome P450 enzymes may also increase individual susceptibility. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, hepatic fibrosis and cirrhosis, veno-occlusive disease, and acute liver failure requiring transplantation. In addition to the potential for hepatotoxicity, drug-drug interactions between herbal medicines and conventional agents may affect the efficacy and safety of concurrent medical therapy. This review focuses on emerging hepatotoxins and patterns of liver injury, potential risk factors for herbal hepatotoxicity, and herb-drug interactions. Appropriate reporting and regulatory systems to monitor herbal toxicity are required, in conjunction with ongoing scientific evaluation of the potential benefits of phytotherapy.

Adverse Drug Reaction Reporting Systems↗