Deleterious Effects of Reactive Metabolites

Attia, Sabry M.

doi:10.4161/oxim.3.4.13246

Cited by 161 publications

(120 citation statements)

References 112 publications

(110 reference statements)

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“…Accumulation of these free radicals may cause damage to cellular genome and other critical biomolecules, ultimately inducing mutagenesis and carcinogenesis (Attia 2010). The present study demonstrates that etoposide and merbarone are able to generate reactive oxygen species as determined by measuring the Xuorescence of DCFH-DA-stained sperm cells.…”

Section: Resultsmentioning

confidence: 59%

Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study

Attia

2011

Arch Toxicol

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Two topoisomerase II inhibitors, etoposide and merbarone, were tested for the induction of dominant lethal mutations in male mice. Etoposide was administered at a dosage of 30 or 60 mg/kg. Merbarone was administered at a dosage of 40 or 80 mg/kg. These males were mated at weekly intervals to virgin females for 6 weeks. In the present experiments, regardless of the agent, spermatids appeared to be the most sensitive germ-cell stage to dominant lethal induction. Etoposide and merbarone clearly induced dominant lethal mutations in the early spermatid stage only with the highest tested doses. The mutagenic effects were also directly correlated with reactive oxygen species accumulation as an obvious increase in 2',7'-dichlorofluorescein fluorescence level was noted in the sperm of animals treated with higher doses of etoposide and merbarone. Treatment of male mice with N-acetylcysteine significantly protected mice from etoposide- and merbarone-induced dominant lethality. Moreover, N-acetylcysteine treatment had no antagonizing effect on etoposide- and merbarone-induced topoisomerase II inhibition. Overall, this study provides for the first time that etoposide and merbarone induce dominant lethal mutations in the early spermatid stage through a mechanism that involves increases in oxidative stress. The demonstrated mutagenicity profile of etoposide and merbarone may support further development of effective chemotherapy with less mutagenicity.

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Section: Resultsmentioning

confidence: 59%

Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study

Attia

2011

Arch Toxicol

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“…A large number of drugs have been reported to cause hepatotoxicity, posing a profound challenge to the pharmaceutical industry and regulatory agencies [21,22]. Although the mechanisms underlying drug-induced hepatotoxicity remain poorly understood, it has been widely accepted that in many cases the initial step triggering the progression of hepatotoxicity involves metabolism of a drug to chemically reactive metabolites, which covalently bind to cellular macromolecules (e.g., proteins, nucleic acids and lipids), resulting in irreversible chemical modification, adduct formation and functional impairment [23][24][25].…”

Section: Resultsmentioning

confidence: 99%

Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity

Xuan

Chen

Ning

et al. 2016

Chemico-Biological Interactions

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The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drugtreated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity.

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“…Although several hypotheses to explain them have emerged over the years, the reactions have remained poorly understood. One possibility for a crucial factor of idiosyncratic DILI is drug metabolism-related factors (Amacher, 2006;Attia, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…However, some of the drugs or xenobiotics may be activated to chemically electrophilic reactive metabolites. This bioactivation is known to be the initial event in many drug-induced toxicities, including DILI (Amacher, 2006;Attia, 2010). However, the relationship between the development of idiosyncratic DILI, drug metabolism-related factors (including reactive metabolite formation) has not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries

Sasaki

Yokoi

2018

J. Toxicol. Sci.

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-Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have rarely caused severe adverse reactions, such as fulminant hepatitis, and have been recognized as sources of idiosyncratic DILI. The studies of animal models of idiosyncratic DILIs have produced new knowledge of chronic administration, CYP inductions/inhibitions, glutathione contents, and immune-related factors for the initiation of idiosyncratic DILIs. Considering changes in the drug metabolic profile and detoxification abilities, idiosyncratic DILIs caused by antiepileptic drugs will lead to understanding the mechanisms of these DILIs.

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Deleterious Effects of Reactive Metabolites

Cited by 161 publications

References 112 publications

Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study

Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study

Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity

Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries

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