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Detoxification

About: Detoxification is a research topic. Over the lifetime, 2380 publications have been published within this topic receiving 39669 citations.


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Journal Article
TL;DR: It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for thetreatment of Cushing's syndrome.
Abstract: In increasingly large numbers, drugs, pesticides, herbicides, food additives, and environmental carcinogenic hydrocarbons are being found to stimulate their own metabolism or the metabolism of other compounds. The evidence suggests that foreign chemicals exert this action by increasing the amount of drug-metabolizing enzymes in liver microsomes.Treatment of animals or man with suitable inducers of liver microsomal enzymes accelerates drug metabolism in vivo and alters the duration and intensity of drug action. For instance, barbiturates decrease the anticoagulant activity of coumarin anticoagulants by accelerating their metabolism. This effect requires that the dosage of coumarins be raised to obtain an adequate anticoagulant response, and serious toxicity can result after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose. The stimulatory effect of drugs on their own metabolism often allows the organism to detoxify drugs more rapidly. This effect has considerable importance when it causes drugs to become less toxic and less effective during prolonged administration. However, if a metabolite has more activity than the parent drug, enzyme induction can enhance the drug's action. Enzyme induction may also be important during chronic exposure to environmental carcinogens, such as 3, 4-benzpyrene. The ability of 3, 4-benzpyrene to stimulate its own metabolism in liver, lung, gastrointestinal tract and skin represents an important mechanism for the detoxification of this substance. Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes. Accordingly, treatment of rats with phenobarbital enhances the hydroxylation of androgens, estrogens, glucocorticoids, and progestational steroids by liver microsomes. This effect is paralleled in vivo by enhanced metabolism of steroids to polar metabolites and by a decreased action of steroids such as estradiol, estrone, and progesterone. Recent studies suggest that inducers of liver microsomal enzymes enhance the hydroxylation of steroids in man. Phenobarbital, diphenylhydantoin, and phenylbutazone are examples of drugs that stimulate cortisol hydroxylase activity in guinea pig liver microsomes and enhance the urinary excretion of 6 β-hydroxycortisol in man. Further research is needed to learn whether the stimulatory action of drugs on the metabolism of normal body constituents is harmful or whether it restores a homeostasis that was upset by drug administration. It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for the treatment of Cushing's syndrome. Considerable further work is required to evaluate more completely the effects of liver microsomal enzyme inducers on the metabolism of bilirubin, cortisol, and other normal body constituents in experimental animals and man.

2,869 citations

Book ChapterDOI
TL;DR: There appears to be sufficient enzyme for all three roles in detoxification of glutathione S-transferases; the binding of bilirubin is an example of a major function common to all higher species.
Abstract: The physiological roles of the glutathione S-transferases, by whatever name, seem to result in detoxification As is true of albumin, members of this group of proteins bind an enormous number of compounds that appear to have in common only hydrophobic topography; the binding of bilirubin is an example of a major function common to all higher species If the ligand bears a sufficiently electrophilic center, it will be attacked by the nucleophile GSH; such compounds would be the substrates of the enzyme And should such a ligand be extraordinarily reactive--as, for example, some of the epoxide carcinogens generated by the cytochrome P450-linked, mixed-function oxidases, or even 1-chloro-2,4-dinitrobenzene--then reaction may occur either with GSH or irreversibly with the transferase itself By reason of the wide distribution and high intracellular concentration of these proteins, there appears to be sufficient enzyme for all three roles in detoxification

651 citations

Journal ArticleDOI
TL;DR: The vacuolar glutathione-conjugate transporter shows functional similarities with an ATP-binding cassette transporter, the multidrug resistance-associated protein, present in drug-tolerant human cancer cells.

614 citations

Journal Article
TL;DR: It seems likely that alterations in glutathione metabolism of tumor or host as a result of one therapeutic intervention may affect the outcome of concurrent treatments, and knowledge of these interactions may be useful in designing combination therapy for neoplastic disease.
Abstract: Glutathione, as the chief nonprotein intracellular sulfhydryl, affects the efficacy and interactions of a variety of antineoplastic interventions, mainly through nucleophilic thioether formation or oxidation-reduction reactions. Thus, glutathione plays a role in the detoxification and repair of cellular injury by such diverse agents as mechlorethamine, melphalan, cyclophosphamide, nitrosoureas, 6-thiopurine, 4'-(9-acridinylamino)methanesulfon-m-anisidide, the quinone antibiotics (including Adriamycin, daunorubicin, and mitomycin C), the sesquiterpene lactones (such as vernolepin), and other sulfhydryl-reactive diterpenes (like jatrophone). Glutathione may play a similar role in host and tumor cell responses to radiation, hyperthermia, and the reactive reduction products of oxygen secreted by inflammatory cells. Further, glutathione participates in the formation of toxic metabolites of such chemotherapeutics as azathioprine and bleomycin and may affect the cellular uptake of other agents, such as methotrexate. It seems likely that alterations in glutathione metabolism of tumor or host as a result of one therapeutic intervention may affect the outcome of concurrent treatments. Knowledge of these interactions may be useful in designing combination therapy for neoplastic disease.

521 citations


Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20222
2021102
202092
201989
201890
201777