A5042199020- Drug-Induced Hepatotoxicity and Protection
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Pharmacology and Obesity Treatment
- Liver Disease Diagnosis and Treatment
- Liver Disease and Transplantation
- Cell death mechanisms and regulation
- Computational Drug Discovery Methods
- Diet and metabolism studies
- Liver physiology and pathology
- S100 Proteins and Annexins
- Neuroscience and Neuropharmacology Research
- Adipose Tissue and Metabolism
- Cannabis and Cannabinoid Research
- Alcohol Consumption and Health Effects
- Carcinogens and Genotoxicity Assessment
- Pharmaceutical Practices and Patient Outcomes
- Sulfur Compounds in Biology
- Mitochondrial Function and Pathology
- Antibiotics Pharmacokinetics and Efficacy
- Analytical Chemistry and Chromatography
- Trace Elements in Health
- Animal testing and alternatives
- Synthesis and Characterization of Heterocyclic Compounds
- Clinical Nutrition and Gastroenterology
Wayne State University
2002-2013
Eugene Applebaum College of Pharmacy and Health Sciences
2010-2013
University of New Mexico
1988-1997
The University of Texas Medical Branch at Galveston
1994
Karolinska Institutet
1994
Emory University
1994
Bristol-Myers Squibb (Germany)
1994
State University of New York
1993
The University of Sydney
1993
St. James's Hospital
1991
N-Acetylcysteine is the drug of choice for treatment an acetaminophen overdose. It thought to provide cysteine glutathione synthesis and possibly form adduct directly with toxic metabolite acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, other mechanisms action such as reduction quinoneimine might be responsible clinical efficacy N-acetylcysteine. After administration rats (1 g/kg) intraduodenally (i.d.) [35S]-N-acetylcysteine (1.2 g/kg...
Adding ascorbic acid to microsomal incubations containing acetaminophen inhibited covalent binding of the reactive metabolite. and cysteine markedly decreased acetaminophen-cysteine adduct formation. Ascorbic addition aqueous N-hydroxyacetaminophen similarly nonenzymatic formation an adduct. Therefore, chemical reactions responsible for decomposition yield adducts were examined. In solutions above pH 7, rapidly dehydrated N-acetyl-p-benzoquinoneimine. absence reducing compounds...
Acetylhydrazine, a metabolite of isoniazid, widely used antituberculosis drug, and isopropylhydrazine, iproniazid, an antidepressant removed from clinical use because high incidence liver injury, were oxidized by cytochrome P-450 enzymes in human rat microsomes to highly reactive acylating alkylating agents. Covalent binding these metabolites macromolecules paralleled hepatic cellular necrosis. The formed probably other monosubstituted hydrazines are electrophiles.
The revelation that many covalent binding estimates are falsely low due to flawed normalization discloses protection by N-acetyl-L-cysteine against acetaminophen hepatotoxicity is accompanied routinely a 50 80% decline in arylation. Elevated glutathione may be responsible for inhibiting but above-normal concentrations have never been demonstrated vivo after treatment or separated adequately from other possible hepatoprotective actions including direct reduction of the toxic metabolite...
Ca2+ accumulates in the nucleus and DNA undergoes enzymatic cleavage into internucleosome-length fragments before acetaminophen dimethylnitrosamine produce hepatic necrosis vivo toxic cell death vitro. However, Ca(2+)-endonuclease fragmentation of is characteristic apoptosis, a type considered biochemically functionally distinct from death. The present studies investigate as critical event by testing whether Ca(2+)-calmodulin antagonist chlorpromazine channel blocker verapamil prevent...
Experiments were designed to test whether the protective effect of N-acetylcysteine against acetaminophen hepatotoxicity precedes arylation tissue or protection occurs after tissue. Investigation potential postarylation actions showed that was unable attenuate liver necrosis caused by several other hepatotoxins act through chemically reactive metabolites. Furthermore, varying time and route treatment indicated late mortality probably a consequence pharmacokinetic factors rather than...
Cytochrome P450IIE1 (IIE1) is a microsomal xenobiotic-activating enzyme that inducible not only by various chemical agents but also fasting and diabetes. Using rat model mimics human obesity, we have found hepatic IIE1 levels are increased this common clinical disorder. Liver microsomes from rats made obese feeding with an energy-dense diet displayed elevated aggregate P450 content (+28%) enhanced catalytic activities associated IIE1, including low-Km N-nitrosodimethylamine demethylation...
Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and variety of food sources. has antiinflammatory antioxidant properties, also potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an agent, since particularly difficult cancer treat eradicate. Our data show that induces dose- time-dependent death cells, measured lactate...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChromatographic Separation and Determination of Dicarboxylic Acids C4 to C10Takeru Higuchi, N. C. Hill, G. B. CorcoranCite this: Anal. Chem. 1952, 24, 3, 491–493Publication Date (Print):March 19, 1952Publication History Published online1 May 2002Published inissue 19 March 1952https://pubs.acs.org/doi/10.1021/ac60063a015https://doi.org/10.1021/ac60063a015research-articleACS PublicationsRequest reuse permissionsArticle...
N-acetylcysteine is the drug of choice for treatment acetaminophen poisoning, yet mechanism protection in vivo unknown. Prevention liver injury could result from decreased production toxic intermediate(s), increased capacity to detoxify intermediate(s) or ability tissue withstand even repair molecular damage caused by species. Treatment mice with (1200 mg/kg p.o.) was found prevent hepatic 1000 p.o. acetaminophen. Possible mechanisms this hepatoprotective effect were examined measurement at...
The overfed rat served as the animal model for examining influence of obesity on hepatotoxic and nephrotoxic potential metabolically activated drugs, acetaminophen prototype drug. Weanling Sprague-Dawley rats were given a standard pellet diet or semisynthetic, energy-dense designed to produce obesity. After 24 weeks, when outweighed controls by more than 50%, animals received 710 mg/kg i.p., based total body weight. Toxicity evaluation included biochemical signs organ injury over first hr...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChromatographic Separation and Determination of Straight-Chain Saturated Monocarboxylic Acids C1 through C10 Dicarboxylic C11 C16G. B. CorcoranCite this: Anal. Chem. 1956, 28, 2, 168–171Publication Date (Print):February 1, 1956Publication History Published online1 May 2002Published inissue 1 February 1956https://pubs.acs.org/doi/10.1021/ac60110a006https://doi.org/10.1021/ac60110a006research-articleACS PublicationsRequest reuse permissionsArticle...
Several hepatotoxic agents damage Ca++ regulation and produce toxic cell death in a manner consistent with cause-and-effect relationship; however, vital targets of remain unidentified. Recent results show that DNA may be the chief target during apoptosis, form considered distinct from or necrosis. The present studies explored whether nuclear is lost before dimethylnitrosamine-induced necrosis, attacked by Ca(++)-dependent endonucleases inhibitors Ca(++)-endonuclease activity repair enzyme...
Acetaminophen (N-acetyl-p-aminophenol [APAP]) hepatotoxicity is a process characterized by Ca 2+ deregulation. Cellular functions utilizing as second messenger molecule affect both cytosolic and nuclear signal transduction. Many studies have independently shown - related effects on target molecules in response to toxic doses of APAP; however, the primary resulting liver necrosis has not been determined. We hypothesize that -dependent DNA damage critical event caused alkylating hepatotoxins....