Covalent binding of trans-stilbene to rat liver microsomes

Docks, Edward L.; Krishna, Gopal

doi:10.1016/0006-2952(75)90383-4

Cited by 20 publications

(4 citation statements)

References 15 publications

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“…While some of the common target proteins clearly have important cellular functions, the significance of their modification by reactive intermediates is much less clear. For example, reactive metabolites from p-bromophenol (55), 3′-hydroxyacetanilide (25,(56)(57)(58), and trans-stilbene (23) covalently bind to liver proteins without causing significant hepatotoxicity. In addition, several abundant protein targets for acetaminophen metabolites are also known to be adducted by its nontoxic regioisomer 3′-hydroxyacetanilide (59).…”

Section: And Ref 29)mentioning

confidence: 99%

“…While it is not hard to imagine that such covalent binding events constitute "microlesions" that collectively damage individual cells and hence tissues, it is also not hard to imagine that some such events might have no detectable toxic consequences for the cell. Indeed, a number of compounds are known whose metabolism leads to significant levels of total covalent binding without causing apparent cytotoxicity (23)(24)(25). A significant question that arises in this light is "for a given chemical toxicant, which adducts are toxicologically significant?"…”

Section: Introductionmentioning

confidence: 99%

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A Proteomic Analysis of Bromobenzene Reactive Metabolite Targets in Rat Liver Cytosol in Vivo

Koen

Gogichaeva

Alterman

et al. 2007

Chem. Res. Toxicol.

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Metabolic activation and protein covalent binding are early and apparently obligatory events in the cytotoxicity of many simple organic chemicals including drugs and natural products. Although much has been learned about the chemistry of reactive metabolite formation and reactivity toward protein nucleophiles, progress in identifying specific protein targets for reactive metabolites of various protoxins has been much slower. We previously reported nine microsomal and three cytosolic proteins as targets for reactive metabolites of bromobenzene in rat liver. These results, and contemporary work by others, indicate that protein covalent binding is not totally random in cells. Moreover, as protein targets for other protoxins were identified, little commonality of target proteins became apparent. In the present work, we used two-dimensional gel electrophoresis to separate liver cytosolic proteins from rats treated with 14C-bromobenzene; 110 of the 836 observed spots contained measurable radioactivity that varied over a 600-fold range of adduct density. Of these 110 spots, in-gel digestion coupled with mass spectrometry identified apparently single proteins in 57 spots. A few other spots clearly contained more than one identifiable protein, and in several cases, the same protein was identified in several spots having different apparent molecular masses and/or pI. Altogether, 33 unique new protein targets for bromobenzene metabolites were identified and compared to those known for acetaminophen, naphthalene, butylated hydroxytoluene, benzene, thiobenzamide, and halothane via a target protein database available at http://tpdb.medchem.ku.edu:8080/protein_database/. With increasing numbers of target proteins becoming known, more commonality in targeting by reactive metabolites from diverse chemical agents may be seen. Such commonality may help to separate toxicologically significant covalent binding events from a background of covalent binding that is toxicologically inconsequential.

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Section: And Ref 29)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Proteomic Analysis of Bromobenzene Reactive Metabolite Targets in Rat Liver Cytosol in Vivo

Koen

Gogichaeva

Alterman

et al. 2007

Chem. Res. Toxicol.

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“…Thus, the greater S-alkylating properties of quinone as compared to epoxide metabolites of bromobenzene need not necessarily imply a greater role for quinones in the toxic mechanism of the halobenzenes. Trans-Stilbene (23) and m-hydroxyacetanilide (24) become covalently bound to liver tissue but do not elicit hepatotoxicity. Monks et al (4), comparing the toxicity and covalent binding of bromobenzene and 4-bromophenol in vivo, concluded that hepatotoxicity was more likely to be mediated by bromobenzene 3,4-epoxide, with 4-bromophenol giving rise to alkylating, but nontoxic (probably quinone), metabolites.…”

Section: Alkylating Properties Of Epoxides and Quinonesmentioning

confidence: 99%

Cytochrome P450-Catalyzed Oxidation of Halobenzene Derivatives

Rietjens

Besten

Hanzlik

et al. 1997

Chem. Res. Toxicol.

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“…As in the case of bromobenzene and acetaminophen hepatotoxicity, a threshold dose must be achieved before tissue damage is observed (15). Significant amounts of trans-stilbene (a weak synthetic estrogen) are bound to liver and kidney protein up to doses which deplete glutathione levels; however, no significant liver or kidney histopathological changes are seen (16). Acetyl-m-aminophenol, a regioisomer of acetyl-p-aminophenol (APAP) possessing similar analgesic and antipyretic properties, was approximately 10 times less toxic to cultured mouse hepatocytes despite a greater extent of protein binding in this system (17).…”

Section: Introductionmentioning

confidence: 99%

Covalent Protein Adducts of Hydroquinone in Tissues from Rats: Quantitation of Sulfhydryl-Bound Forms following Single Gavage or Intraperitoneal Administration or Repetitive Gavage Administration

et al. 2000

Chem. Res. Toxicol.

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The current studies were conducted to investigate the degree and type of protein binding of hydroquinone (HQ) in the rat following single oral or intraperitoneal (ip) or repeated oral administrations. Male or female F-344 rats or male SD rats received a single dose of HQ at 0, 25, 50, or 100 mg/kg by either gavage or ip injection (SD rats only). In addition, male or female F-344 or male SD rats received HQ by gavage for 6 weeks (5 days/week) at 0, 25, or 50 mg/kg/day. Sulfhydryl-bound HQ was quantitated in protein from blood, kidneys, livers, or spleens 24 h after treatment using an alkaline permethylation procedure. The amount of total protein-S adducts increased with increasing dose in all the tissues that were assayed. Female rats had higher levels of adducts in blood, livers, and kidneys than did male rats when they were treated orally. Male F-344 rats treated orally had elevated levels of adducts in these same tissues compared to SD rats treated orally. For all genders and strains of rats and for all treatment regimens, mono-adducts predominated in livers (>72% of total). In the kidneys, tri- and tetrasubstituted adducts predominated with the summation accounting for >60% of the total. Ip administration of HQ resulted in significantly elevated levels of adducts in all the tissues that were examined, with the greatest increases seen for protein from blood and spleens. Levels of protein-S adducts of HQ in rat kidney following a single gavage administration correlated well with previously published differences in acute HQ nephrotoxicity in rats (female F-344 rat > male F-344 rat > male SD rat). Elevated levels of HQ protein-S adducts following repeated gavage administration did not correlate to measurable clinical signs of nephrotoxicity. Evidence is presented suggesting a possible role for the prostaglandin H synthase complex in the metabolic activation of HQ. In addition, protein arylation alone cannot account for the greater sensitivity of male F-344 rats toward chronic administration of HQ. The sensitivity of male F-344 rats to HQ is likely due to other factors, including the incidence and severity of chronic progressive nephropathy.

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Covalent binding of trans-stilbene to rat liver microsomes

Cited by 20 publications

References 15 publications

A Proteomic Analysis of Bromobenzene Reactive Metabolite Targets in Rat Liver Cytosol in Vivo

A Proteomic Analysis of Bromobenzene Reactive Metabolite Targets in Rat Liver Cytosol in Vivo

Cytochrome P450-Catalyzed Oxidation of Halobenzene Derivatives

Covalent Protein Adducts of Hydroquinone in Tissues from Rats: Quantitation of Sulfhydryl-Bound Forms following Single Gavage or Intraperitoneal Administration or Repetitive Gavage Administration

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