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27 results on '"Szakacs, Juliana G."'

1. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Author

Yohe, Herbert C., O'Hara, Kimberley A., Hunt, Jane A., Kitzmiller, Tamar J., Wood, Sheryl G., Bement, Jenna L., Bement, William J., Szakacs, Juliana G., Wrighton, Steven A., Jacobs, Judith M., Kostrubsky, Vsevolod, Sinclair, Peter R., and Sinclair, Jacqueline F.

Subjects
Endotoxins -- Research, Endotoxins -- Properties, Tyrosine -- Analysis, Tyrosine -- Research, Biological sciences
Abstract

The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-[alpha]. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-[alpha]. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity. endotoxin; nitrotyrosine

Published
2006

13. Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Author

Wolf, Kristina K., primary, Wood, Sheryl G., additional, Allard, Jenna L., additional, Hunt, Jane A., additional, Gorman, Nadia, additional, Walton-Strong, Brooke W., additional, Szakacs, Juliana G., additional, Duan, Su X., additional, Hao, Qin, additional, Court, Michael H., additional, von Moltke, Lisa L., additional, Greenblatt, David J., additional, Kostrubsky, Vsevolod, additional, Jeffery, Elizabeth H., additional, Wrighton, Steven A., additional, Gonzalez, Frank J., additional, Sinclair, Peter R., additional, and Sinclair, Jacqueline F., additional

Published
2007
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17. MORTALITY AND PATHOLOGICAL FINDINGS IN C (OPITZ TRIGONOCEPHALY) SYNDROME

Author

Opitz, John M., primary, Putnam, Angelica R., additional, Comstock, Jessica M., additional, Chin, Steven, additional, Byrne, Janice L. B., additional, Kennedy, Anne, additional, Frikke, Maureen J., additional, Bernard, Chantal, additional, Albrecht, Steffen, additional, Kaloustian, Vazken Der, additional, and Szakacs, Juliana G., additional

Published
2006
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18. Genetic factors influence ethanol-induced uroporphyria in Hfe (—/—) mice

Author

Gorman, Nadia, primary, Trask, Heidi W., additional, Bement, William J., additional, Szakacs, Juliana G., additional, Elder, George H., additional, Balestra, Dominic, additional, Jacobs, Nicholas J., additional, Jacobs, Judith M., additional, Sinclair, Jacqueline F., additional, Gerhard, Glenn S., additional, and Sinclair Ph.D., Peter R., additional

Published
2004
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20. Genetic factors influence ethanol-induced uroporphyria inHfe(?/?) mice

Author

Gorman, Nadia, primary, Trask, Heidi W., additional, Bement, William J., additional, Szakacs, Juliana G., additional, Elder, George H., additional, Balestra, Dominic, additional, Jacobs, Nicholas J., additional, Jacobs, Judith M., additional, Sinclair, Jacqueline F., additional, Gerhard, Glenn S., additional, and Sinclair, Peter R., additional

Published
2004
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24. Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type and Cyp2e1(–/–) Mice

Author

Wolf, Kristina K., Wood, Sheryl G., Allard, Jenna L., Hunt, Jane A., Gorman, Nadia, Walton-Strong, Brooke W., Szakacs, Juliana G., Duan, Su X., Hao, Qin, Court, Michael H., von Moltke, Lisa L., Greenblatt, David J., Kostrubsky, Vsevolod, Jeffery, Elizabeth H., Wrighton, Steven A., Gonzalez, Frank J., Sinclair, Peter R., and Sinclair, Jacqueline F.

Abstract

CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(–/–) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(–/–) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(–/–) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(–/–) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(–/–) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.

Published
2007
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25. ROLE OF THE NUCLEAR RECEPTOR PREGNANE X RECEPTOR IN ACETAMINOPHEN HEPATOTOXICITY

Author

Wolf, Kristina K., Wood, Sheryl G., Hunt, Jane A., Walton-Strong, Brooke W., Yasuda, Kazuto, Lan, Lubin, Duan, Su X., Hao, Qin, Wrighton, Steven A., Jeffery, Elizabeth H., Evans, Ronald M., Szakacs, Juliana G., von Moltke, Lisa L., Greenblatt, David J., Court, Michael H., Schuetz, Erin G., Sinclair, Peter R., and Sinclair, Jacqueline F.

Abstract

The pregnane X receptor (PXR) is a transcriptional regulator of xenobiotic metabolizing enzymes, including cytochrome P450 3A (CYP3A), and transporters. Pretreatment of mice and rats with inducers of CYP3A increases acetaminophen (APAP) hepatotoxicity. In untreated mice, the amount of hepatic CYP3A11 mRNA is 4-fold greater in PXR(–/–)mice compared to wild-type mice (Guo et al., 2003), a finding anticipated to increase APAP hepatotoxicity in PXR(–/–)mice. We investigated APAP hepatotoxicity in wild-type and PXR(–/–)mice in a C57BL/6 background, with APAP administered by gavage. Despite a 2.5-fold higher level of total hepatic CYP3A protein and a 3.6-fold higher level of CYP3A activity compared to wild-type mice, PXR(–/–)mice were less sensitive to APAP hepatotoxicity. Hepatic levels of CYP2E1 were identical in the two mouse lines, but hepatic CYP1A2 levels were 3-fold greater in wild-type mice compared to PXR(–/–)mice. Caffeine, an inhibitor of CYP1A2 activity and an enhancer of CYP3A activity, decreased APAP hepatotoxicity in wild-type mice. APAP uptake was 1.5-fold greater in wild-type mice compared to PXR(–/–)mice. No significant differences in the formation of APAP glucuronide and sulfate-conjugated metabolites were observed between wild-type and PXR(–/–)mice. Glutathione levels were similar in the two mouse lines and were transiently decreased to similar amounts after APAP administration. Our finding that APAP hepatotoxicity was decreased in PXR(–/–)mice indicates that PXR is an important modulator of APAP hepatotoxicity, through positive modulation of constitutive CYP1A2 expression and possibly through increased APAP absorption.

Published
2005
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27. Chemopreventive activity of selenocysteine prodrugs against tobacco-derived nitrosamine (NNK) induced lung tumors in the A/J mouse.

Author

Li L, Xie Y, El-Sayed WM, Szakacs JG, Franklin MR, and Roberts JC

Subjects
Animals, Body Weight, Female, Glutathione Peroxidase metabolism, Liver enzymology, Liver metabolism, Lung Neoplasms chemically induced, Mice, Organ Size, Selenium blood, Selenium metabolism, Carcinogens toxicity, Lung Neoplasms prevention & control, Nitrosamines toxicity, Prodrugs administration & dosage, Selenocysteine administration & dosage, Nicotiana chemistry
Abstract

Prodrugs of L-selenocysteine have potential utility in cancer chemoprevention. This study reports the efficacy of three selenazolidine-4(R)-carboxylic acids, (2-unsubstituted, 2-oxo, and 2-methyl derivatives; SCA, OSCA, and MSCA, respectively) against tobacco-related lung tumorigenesis in a mouse model. Seven days after initiation of an AIN-76A diet supplemented with sodium selenite (5 ppm Se), L-selenomethionine (3.75 ppm Se), Se-methyl-L-selenocysteine (3 ppm Se), L-selenocystine (15 ppm Se), SCA (15 ppm Se), OSCA (15 ppm Se), or MSCA (15 ppm Se), mice received 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 10 micromol, i.p.). After an additional 16 weeks on the diets, two compounds, OSCA and selenocystine, significantly reduced lung adenoma multiplicity from 7.2 tumors per mouse in the NNK group to 4.5 and 4.6 tumors per mouse, respectively. Neither selenium concentration nor glutathione peroxidase activity in either RBCs or liver served as surrogate indicators of tumor reduction. Hepatic selenium levels were significantly elevated by all selenium-containing compounds except Se-methyl-L-selenocysteine and SCA; RBC selenium levels by all except sodium selenite and MSCA. With the exception of L-selenomethionine, RBC glutathione peroxidase activity was increased along with the elevated selenium levels. Hepatic glutathione peroxidase activity was elevated by all Se-compounds except SCA. The two compounds showing significant tumor reduction (OSCA and selenocystine) were the only two compounds that showed ubiquity of changes, elevating both selenium levels and GPx activity in both liver and RBC., ((c) 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:396-405, 2005)

Published
2005
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