Metabolic Activation of Tris(2,3-dibromopropyl)phosphate to Reactive Intermediates .II. Covalent Binding, Reactive Metabolite Formation, and Differential Metabolite-Specific DNA Damage in Vivo

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.

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Hearing, reactive metabolite formation, and oxidative stress in cochleae after a single acute overdose of acetaminophen: an in vivo study

Toxicology Mechanisms and Methods ◽

10.3109/15376516.2015.1122136 ◽

2016 ◽

Vol 26 (2) ◽

pp. 104-111 ◽

Cited By ~ 5

Author(s):

Mitchell R. McGill ◽

Stefanie Kennon-McGill ◽

Dianne Durham ◽

Hartmut Jaeschke

Keyword(s):

Oxidative Stress ◽

In Vivo Study ◽

Reactive Metabolite ◽

Metabolite Formation ◽

Acute Overdose ◽

And Oxidative Stress

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Faculty Opinions recommendation of Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1079833.532758 ◽

2007 ◽

Author(s):

Michael Cunningham

Keyword(s):

Metabolic Activation ◽

Reactive Intermediates ◽

Reactive Intermediate ◽

Glutathione Conjugate

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Prediction of in Vivo Potential for Metabolic Activation of Drugs into Chemically Reactive Intermediate: Correlation of in Vitro and in Vivo Generation of Reactive Intermediates and in Vitro Glutathione Conjugate Formation in Rats and Humans

Chemical Research in Toxicology ◽

10.1021/tx060234h ◽

2007 ◽

Vol 20 (3) ◽

pp. 455-464 ◽

Cited By ~ 91

Author(s):

Noriko Masubuchi ◽

Chie Makino ◽

Nobuyuki Murayama

Keyword(s):

Metabolic Activation ◽

Reactive Intermediates ◽

Reactive Intermediate ◽

Glutathione Conjugate

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Metabolic activation of acetylenic substituents to derivatives in the rat causing the loss of hepatic cytochrome P-450 and haem

Biochemical Journal ◽

10.1042/bj1740853 ◽

1978 ◽

Vol 174 (3) ◽

pp. 853-861 ◽

Cited By ~ 51

Author(s):

Ian N. H. White

Keyword(s):

Covalent Binding ◽

Metabolic Activation ◽

Microsomal Protein ◽

Significant Loss ◽

Microsomal Cytochrome ◽

Rf Values ◽

Green Pigments ◽

Cytochrome P 450

1. A number of acetylenic-substituted steroidal and non-steroidal compounds, including 2,2-dipropargylacetamide, pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol (Danazol) and acetylene gas, when administered to rats in vivo brought about a decrease in the concentrations of hepatic microsomal cytochrome P-450 and haem. Abnormal haem-breakdown products, ‘green pigments’, and porphyrins accumulated in the livers of these animals. 2. For loss of microsomal cytochrome P-450 to occur in vitro, metabolic activation of the acetylenic substituent was necessary. The enzyme system responsible required NADPH and air, and was induced by pretreatment of rats with phenobarbitone; these are characteristics typical of the microsomal mixed-function oxidases. 3. When rats were dosed with 17α-ethynyl-17β-hydroxyandrost-4-en-3-one (ethynyltestosterone, 1mmol/kg) the pattern of green pigments extracted from the liver 4h after dosing and separated by t.l.c. was quite different from that in rats given 17β-hydroxy-17α-vinylandrost-4-en-3-one (vinyltestosterone), suggesting that reduction of the unsaturated triple bond to a double bond is not normally part of the metabolic activation pathway of the acetylenic substituent. 4. The green pigments extracted from the livers of rats 4h after the administration of the acetylenic-substituted compounds (1mmol/kg) when separated by silica-gel t.l.c. had variable RF values. The number and distribution of green pigments was characteristic for each compound examined. There was little correlation between the total loss of hepatic microsomal haem and the apparent intensity of the green pigments seen on the thin-layer chromatograms. 5. After incubation of [14C]acetylene in vitro with microsomal preparations from phenobarbitone-pretreated rats and a NADPH-generating system, no significant covalent binding to microsomal protein was detected over a 30min incubation period, although under similar conditions there was a significant loss of cytochrome P-450.

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