A prospective on covalent binding and toxicity

Gillette, James R.; Pohl, Lance R.

doi:10.1080/15287397709529484

Cited by 33 publications

(3 citation statements)

References 22 publications

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“…Among the experimental adverse effects of DBCP, a correlation between necrotic inci-dence4) and protein alkylation or covalent binding of xenobiotics with proteins has been well elucidated in this decade. 12,27) In regard to the dominant lethality8)9) and chromosomal abberation, 35) G. A. Sega and J. G. Owens has recently deduced an interesting conclusion from their work on molecular dosimetry of ethyl methanesulfonate (a well known alkylating agent, EMS) in mice germ cells.16) They proposed a model that ethylation of cysteine sulfhydryl groups contained in mouse-sperm protamine could block normal disulfide-bond formation, preventing proper chromatin condensation in the sperm nucleus. Stresses in the chromatin structure could then eventually lead to chromosome breakage, with resultant dominant lethality.…”

Section: Discussionmentioning

confidence: 99%

Alkylation of Cellular Macromolecules by Reactive Metabolic Intermediate of DBCP

et al. 1980

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Alkylating potential of DBCP on cellular macromolecules in vitro and in vivo was investigated using 14C-DBCP and male Wistar rats. In studies in vitro with rat-liver-microsome system, incorporation of DBCP-radiocarbon into TCA-and organic-solvents unextractable microsomal proteins was determined. The incorporation was dependent on incubation time, 14C-DBCP concentration, enzymatically active microsomes, NADPH, and oxygen, but it was not affected by sufficient puromycin to inhibit protein synthesis. Addition of SKF-525A, diethyldithiocarbamic acid, cysteine, or glutathione prevented the incorporation, and low concentration of 1, 1, 1-trichloropropane-2, 3-oxide, an inhibitor of epoxide hydrase stimulated the incorporation. When 14C-DBCP (20 mg/ kg) was orally administered to rats, TCA-and organic-solvents unextractable macromolecular residues were formed in rat tissues in parallel to the depletion of hepatic glutathione. Gel-fitration, protease digestion, and 2, 4-dinitrofluorobenzene treating of the liver homogenate showed an existence of radioactive proteins of which primary structure was radiolabeled. DNA isolated from the liver was also radiolabeled. From these results it was concluded that DBCP is oxidatively metabolized to reactive metabolic intermediate(s) by microsomal cytochrome p-450 system and covalently bind with nucleophilic sites of the cellular macromolecules in vitro and also in vivo. And epoxide was proposed as one of the reactive metabolic intermediate(s) responsible for protein alkylation by DBCP.

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Section: Discussionmentioning

confidence: 99%

Alkylation of Cellular Macromolecules by Reactive Metabolic Intermediate of DBCP

et al. 1980

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“…As Gillette has pointed out (Gillette and Pohl 1977), the toxic response is not an inevitable consequence of the formation of covalent associations, but an analysis of such complexes does provide a better understanding of the toxic impact of many drugs. Therefore, evidence of covalent binding of a veterinary drug or of its metabolites with endogenous macromolecules must be taken into account in order to check the toxicity of the substance on target species and to evaluate its potential carcinogenicity.…”

Section: Toxicological Significancementioning

confidence: 98%

Toxicological significance of covalently‐bound residues

Rico

Burgat-Sacaze

1984

Food Additives & Contaminants

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Bound residues may be defined in terms of the nonextractable radioactivity which persists in tissues after administration of radiolabelled compounds to an organism. This fraction is found to contain natural endogenous compounds resulting from incorporation of degradation products of the administered substance into intermediary metabolites (amino acids, carbohydrates etc.). However, 'new' compounds are also found which arise from covalent binding of the administered substance or its metabolites to endogenous macromolecules. The former fraction is nontoxic, but in the second case the nature of the covalent binding is important from the toxicological point of view. It is unspecific and irreversible, and often involves the action of short-lived and highly reactive intermediates. The covalent bond is usually thermodynamically irreversible. A good example is provided by bromobenzene, which binds to proteins via the 3,4-epoxide, which is the hepatotoxic agent. From the above considerations it is possible to distinguish two types of metabolites that may be found in foodstuffs prepared from drug-treated animals. The first are represented by the drug itself and its primary metabolites. These compounds are potentially more or less toxic to the consumer. The second type are the covalently bound metabolites. These have lost their reactivity in an irreversible manner and may be considered to have low toxicity to the consumer as well as low bioavailability. Some examples (trenbolone acetate, aflatoxin, carbaryl) are discussed to support this contention.

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“…Les techniques suivantes, décrites par GUILLETTE et PHOL [8] et admises par d'autres chercheurs, sont applicables pour déterminer si un résidu est en effet lié. On considère qu'un résidu n'est pas lié si on peut_ obtenir la moitié du médicament en appliquant un des points suivants :…”

Section: Les Residus Et Leur Caracterisationunclassified

Les résidus de substances chimiques dans les aliments d’origine animale en Espagne

Anadón¹

1990

bavf

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SUMMARY RESIDUES OF CHEMICAL COMPOUNDS IN FOOD OF ANIMAL ORIGINA number of compounds, environmental contaminants, contaminants resulting from animal treatment, contaminants resulting from meat processing and . packaging and biocontaminants, can lead to the creation of residues in .food of animal origin. The subject of food safety bas been growing in sensitivity over recent years. Pesticide and drug residues in food resulting of compounds applied to slaughter animais have been the object of increasing media attention. Regulations are responding by setting up food safety standards or parameters and residue monitoring programs in animais and fresb meats involving a consumer safety.

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A prospective on covalent binding and toxicity

Cited by 33 publications

References 22 publications

Alkylation of Cellular Macromolecules by Reactive Metabolic Intermediate of DBCP

Alkylation of Cellular Macromolecules by Reactive Metabolic Intermediate of DBCP

Toxicological significance of covalently‐bound residues

Les résidus de substances chimiques dans les aliments d’origine animale en Espagne

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