University of Arkansas for Medical Sciences

About: University of Arkansas for Medical Sciences is a education organization based out in Little Rock, Arkansas, United States. It is known for research contribution in the topics: Population & Health care. The organization has 14077 authors who have published 26012 publications receiving 973592 citations. The organization is also known as: UAMS.

Acetaminophen‐Induced Hepatotoxicity: Role of Metabolic Activation, Reactive Oxygen/Nitrogen Species, and Mitochondrial Permeability Transition

Abstract: Large doses of the analgesic acetaminophen cause centrilobular hepatic necrosis in man and in experimental animals. It has been previously shown that acetaminophen is metabolically activated by CYP enzymes to N-acetyl-p-benzoquinone imine. This species is normally detoxified by GSH, but following a toxic dose GSH is depleted and the metabolite covalently binds to a number of different proteins. Covalent binding occurs only to the cells developing necrosis. Recently we showed that these cells also contain nitrated tyrosine residues. Nitrotyrosine is mediated by peroxynitrite, a reactive nitrogen species formed by rapid reaction between nitric oxide and superoxide and is normally detoxified by GSH. Thus, acetaminophen toxicity occurs with increased oxygen/nitrogen stress. This manuscript will review current data on acetaminophen covalent binding, increased oxygen/nitrogen stress, and mitochondrial permeability transition, a toxic mechanism that is both mediated by and leads to increased oxygen/nitrogen stress.

17 beta-Estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism.

Abstract: We previously reported that 17 beta-estradiol inhibits cytokine-stimulated bioassayable IL-6 and the steady-state level of IL-6 mRNA. To determine the molecular basis of this effect, the transient expression of chloramphenicol acetyltransferase (CAT) reporter plasmid driven by the human IL-6 promoter was studied here in HeLa or murine bone marrow stromal cells (MBA 13.2). 17 beta-estradiol (10(-8) M) completely suppressed stimulated CAT expression in HeLa cells cotransfected with IL-6/CAT constructs and a human estrogen receptor (hER) expression plasmid; but had no effect on reporter expression in HeLa cells not transfected with hER. 17 beta-estradiol also inhibited stimulated expression in MBA 13.2 cells (which express the estrogen receptor constitutively) without the requirement of cotransfection of the hER plasmid. The hormonal effects were indistinguishable between constructs containing a 1.2-kb fragment of the 5' flanking region of the IL-6 gene or only the proximal 225-bp fragment. However, yeast-derived recombinant hER did not bind to the 225-bp segment in DNA band shift assays, nor did the 225-bp fragment compete for binding of an estrogen response element oligonucleotide to yeast-derived estrogen receptor. These data suggest that 17 beta-estradiol inhibits the stimulated expression of the human IL-6 gene through an estrogen receptor mediated indirect effect on the transcriptional activity of the proximal 225-bp sequence of the promoter.

Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase

Abstract: Leukotoxin is a linoleic acic oxide produced by leukocytes and has been associated with the multiple organ failure and adult respiratory distress syndrome seen in some severe burn patients. Leukotoxin has been reported to be toxic when injected into animals intravenously. Herein, we report that this lipid is not directly cytotoxic in at least two in vitro systems. Using a baculovirus expression system we demonstrate that leukotoxin is only cytotoxic in the presence of epoxide hydrolases. In addition, it is the diol metabolite that proves toxic to pulmonary alveolar epithelial cells, suggesting a critical role for the diol in leukotoxin-associated respiratory disease. In vivo data also support the toxicity of leukotoxin diol. For the first time we demonstrate that soluble epoxide hydrolase can bioactivate epoxides to diols that are apparently cytotoxic. Thus leukotoxin should be regarded as a protoxin corresponding to the more toxic diol. This clearly has implications for designing new clinical interventions.