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Acetaminophen reactive intermediates target hepatic thioredoxin reductase.

Jeffrey D. Laskin, Ph.D. - Tue, 01/06/2015 - 15:00

Related Articles

Acetaminophen reactive intermediates target hepatic thioredoxin reductase.

Chem Res Toxicol. 2014 May 19;27(5):882-94

Authors: Jan YH, Heck DE, Dragomir AC, Gardner CR, Laskin DL, Laskin JD

Acetaminophen (APAP) is metabolized in the liver to N-acetyl-p-benzoquinone imine (NAPQI), an electrophilic metabolite known to bind liver proteins resulting in hepatotoxicity. Mammalian thioredoxin reductase (TrxR) is a cellular antioxidant containing selenocysteine (Sec) in its C-terminal redox center, a highly accessible target for electrophilic modification. In the present study, we determined if NAPQI targets TrxR. Hepatotoxicity induced by APAP treatment of mice (300 mg/kg, i.p.) was associated with a marked inhibition of both cytosolic TrxR1 and mitochondrial TrxR2 activity. Maximal inhibition was detected at 1 and 6 h post-APAP for TrxR1 and TrxR2, respectively. In purified rat liver TrxR1, enzyme inactivation was correlated with the metabolic activation of APAP by cytochrome P450, indicating that enzyme inhibition was due to APAP-reactive metabolites. NAPQI was also found to inhibit TrxR1. NADPH-reduced TrxR1 was significantly more sensitive to NAPQI (IC50 = 0.023 μM) than the oxidized enzyme (IC50 = 1.0 μM) or a human TrxR1 Sec498Cys mutant enzyme (IC50 = 17 μM), indicating that cysteine and selenocysteine residues in the redox motifs of TrxR are critical for enzyme inactivation. This is supported by our findings that alkylation of reduced TrxR with biotin-conjugated iodoacetamide, which selectively reacts with selenol or thiol groups on proteins, was inhibited by NAPQI. LC-MS/MS analysis confirmed that NAPQI modified cysteine 59, cysteine 497, and selenocysteine 498 residues in the redox centers of TrxR, resulting in enzyme inhibition. In addition to disulfide reduction, TrxR is also known to mediate chemical redox cycling. We found that menadione redox cycling by TrxR was markedly less sensitive to NAPQI than disulfide reduction, suggesting that TrxR mediates these reactions via distinct mechanisms. These data demonstrate that APAP-reactive metabolites target TrxR, suggesting an additional mechanism by which APAP induces oxidative stress and hepatotoxicity.

PMID: 24661219 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

Radiation-induced Lung Injury and Inflammation in Mice: Role of Inducible Nitric Oxide Synthase and Surfactant Protein D.

Jeffrey D. Laskin, Ph.D. - Mon, 01/05/2015 - 03:00

Radiation-induced Lung Injury and Inflammation in Mice: Role of Inducible Nitric Oxide Synthase and Surfactant Protein D.

Toxicol Sci. 2014 Dec 30;

Authors: Malaviya R, Gow AJ, Francis M, Abramova EV, Laskin JD, Laskin DL

Reactive nitrogen species (RNS) generated after exposure to radiation have been implicated in lung injury. Surfactant protein D (SP-D) is a pulmonary collectin that suppresses inducible nitric oxide synthase (iNOS) mediated RNS production. Herein, we analyzed the role of iNOS and SP-D in radiation-induced lung injury. Exposure of wild type (WT) mice to gamma radiation (8 Gy) caused acute lung injury and inflammation, as measured by increases in bronchoalveolar lavage (BAL) protein and cell content at 24 h. Radiation also caused alterations in SP-D structure at 24 h and 4 wk post exposure. These responses were blunted in iNOS(-/-) mice. Conversely, loss of iNOS had no effect on radiation-induced expression of phospho-H2A.X or tumor necrosis factor (TNF)-α. Additionally, at 24 h post radiation, cyclooxygenase expression and BAL lipocalin-2 levels were increased in iNOS(-/-) mice, and heme oxygenase (HO)-1(+) and Ym1(+) macrophages were evident. Loss of SP-D resulted in increased numbers of enlarged HO-1(+) macrophages in the lung following radiation, along with upregulation of TNF-α, CCL2 and CXCL2, while expression of phospho-H2A.X was diminished. To determine if RNS play a role in the altered sensitivity of SP-D(-/-) mice to radiation, iNOS(-/-)/SP-D(-/-) mice were used. Radiation-induced injury, oxidative stress and tissue repair were generally similar in iNOS(-/-)/SP-D(-/-) and SP-D(-/-) mice. In contrast, TNF-α, CCL2 and CXCL2 expression was attenuated. These data indicate that although iNOS is involved in radiation-induced injury and altered SP-D structure, in the absence of SP-D, it functions to promote proinflammatory signaling. Thus, multiple inflammatory pathways contribute to the pathogenic response to radiation.

PMID: 25552309 [PubMed - as supplied by publisher]

Categories: Publications from UCDPER Members

Hospital disaster response using business impact analysis

Environmental/Disaster News - Mon, 01/05/2015 - 03:00

Prehospital and Disaster Medicine