Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1.
Journal Title: Pharmacological Reports - Year 2012, Vol 64, Issue 4
Abstract
Background: Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end-stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis). Methods: Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control. Results: Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up-regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line. Conclusions: As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes.
Authors and Affiliations
Mateusz Kurzawski, Violetta Dziedziejko, Mariola Post, Maciej Wójcicki, Elżbieta Urasińska, Janusz Miętkiewski, Marek Droździk
Keywords
Related Articles
- EP ID EP98126
- DOI -
- Views 61
- Downloads 0
Effect of natalizumab on oxidative damage biomarkers in relapsing-remitting multiple sclerosis.
Background: Natalizumab is a monoclonal antibody used to treat multiple sclerosis. This study sought to determine whether the protective action of natalizumab involved a reduction in oxidative damage. Methods: Twenty-two...
Effectiveness of lipid-lowering therapy with statins for secondary prevention of atherosclerosis - guidelines vs. reality.
Background: The aim of the study was to analyze the effectiveness of lipid-lowering therapy and therapeutic decisions made by physicians for patients not achieving LDL targets. Methods: 11,768 patients undergoing therapy...
Influence of chronic stress on brain corticosteroid receptors and HPA axis activity.
Background: Disruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study,...
Involvement of spinal PKA/CREB signaling pathway in the development of bone cancer pain.
Background: It has been shown that spinal PKA/CREB signaling pathway is involved in neuropathic and inflammatory pain, but its effects on bone cancer pain have not previously been investigated. The aim of this study was...
Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins.
Background: Recent studies have shown that anisomycin significantly inhibits mammalian cell proliferation, but its mechanism remains unclear. In this study, Jurkat T cells were used to first explore a relationship betwee...