Mutagenicity of diphenylhydantoin and some of its metabolites towards Salmonella typhimurium strains

Sezzano, P.; Raimondi, Alessandro; Arboix, M.; Pantarotto, C.

doi:10.1016/0165-7992(82)90046-x

Cited by 24 publications

(8 citation statements)

References 7 publications

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“…If not repaired, oxidative modifications to DNA have been shown to disrupt transcription, translation, and replication, and to give rise to mutations and ultimately cell death (Ames et al, 1993). In bacterial studies, mutagenicity initiated by phenytoin is dependent upon P450-catalyzed enzymatic bioactivation, requiring preincubation with a metabolic activating system (S9 liver fraction) (Sezzano et al, 1982). However, a subsequent study gave conflicting results as phenytoin was not mutagenic in all bacterial strains tested (Leonard et al, 1984).…”

Section: Discussionmentioning

confidence: 97%

Oxidative Stress-Induced Homologous Recombination As a Novel Mechanism for Phenytoin-Initiated Toxicity

Winn

Kim²,

Nickoloff³

2003

J Pharmacol Exp Ther

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Although the mechanism(s) of phenytoin-initiated toxicity is unknown, phenytoin can be enzymatically bioactivated to a reactive intermediate leading to increased formation of reactive oxygen species, which can damage essential macromolecules, including DNA. The oxidation of DNA can induce DNA doublestrand breaks (DSBs), which may be repaired through homologous recombination. Increased levels of DSBs may induce hyper-recombination, leading to deleterious genetic changes. We hypothesize that these genetic changes mediate phenytoininitiated toxicity. To investigate this hypothesis we used a Chinese hamster ovary cell line containing a neo direct repeat recombination substrate to determine whether phenytoin-initiated DNA oxidation increases homologous recombination.Cells were treated with 0 to 800 M phenytoin for 5 or 24 h, and homologous recombination frequencies and recombinant product structures were determined. Phenytoin-initiated DNA oxidation was determined by measuring the formation of 8-hydroxy-2Ј-deoxyguanosine. We demonstrate that phenytoin increases both DNA oxidation and homologous recombination in a concentration-and time-dependent manner. All recombination products analyzed arose via gene conversion without associated crossover. Our data demonstrate that phenytoin-initiated DNA damage can induce homologous recombination, which may be a novel mechanism mediating phenytoin-initiated toxicity.

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Section: Discussionmentioning

confidence: 97%

Oxidative Stress-Induced Homologous Recombination As a Novel Mechanism for Phenytoin-Initiated Toxicity

Winn

Kim²,

Nickoloff³

2003

J Pharmacol Exp Ther

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“…Moreover, other epoxide metabolites of CBZ (Letratanangkoon and Horning, 1982) as well as the putative epoxide of DPH (Martz et al, 1977) might be involved. The epoxide of DPH is held to be responsible for an increase in congenital anomalies in mice when detoxification by epoxide hydratase is inhibited (Martz et al, 1977) and for the mutagenicity of DPH in the Ames test (Sezzano et al, 1981). Future prospective studies of the offspring of epileptic mothers, including determination of metabolites of antiepileptic drugs, during the first trimester of pregnancy should provide more insight.…”

Section: Discussionmentioning

confidence: 99%

Teratogenicity of Antiepileptic Drug Combinations with Special Emphasis on Epoxidation (of Carbamazepine)

1984

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A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.

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“…Phenytoin (5,5-diphenyl-2,4-imidazolidinedione; diphenylhydantoin; PHT) has been widely used as a highly effective antiepileptic drug (AED) for 50 years. In recent years, PHT has been suspected of mutagenicity, but the existing evidence is equivocal or contradictory: The slight increase in frameshift mutations observed by Sezzano et al (1982) using the Ames test in Salmonella typhimurium was not confrmed by Leonard et al (1984). Genotoxicity assessment by micronucleus test yielded an increase in polychromatic erythrocytes in fetal Swiss mice following PHT administration to the dams (Barcellona et al, 1987).…”

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confidence: 99%

Lack of Sister Chromatid Exchange Induction in Phenytoin‐Treated Patients with Epilepsy

Schaumann¹,

Winge²,

Garry

1989

Epilepsia

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Phenytoin (PHT) has been suspected of having a mutagenic effect with chronic administration, but the existing evidence is equivocal. Contradictory results have been obtained using different testing systems. Sister chromatid exchange (SCE), a sensitive indicator of genotoxic environmental influences, has been used in only a few limited studies of PHT users, with varying results. The present study was designed to evaluate the potential mutagenicity of PHT in a more objective and reliable way than has been done previously. Following careful screening procedures, 16 adult male patients with epilepsy receiving long-term PHT monotherapy and 16 healthy controls were selected for a study of SCE frequencies in peripheral lymphocytes. The patients and controls were matched for sex, age, and smoking habits. Strict exclusionary criteria were observed, including all factors known to affect or suspected of affecting the SCE frequencies. Statistical analyses did not reveal any significant differences between the SCE rates of PHT-treated patients and controls, indicating a lack of PHT mutagenicity as expressed by induction of SCE in adults.

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Mutagenicity of diphenylhydantoin and some of its metabolites towards Salmonella typhimurium strains

Cited by 24 publications

References 7 publications

Oxidative Stress-Induced Homologous Recombination As a Novel Mechanism for Phenytoin-Initiated Toxicity

Oxidative Stress-Induced Homologous Recombination As a Novel Mechanism for Phenytoin-Initiated Toxicity

Teratogenicity of Antiepileptic Drug Combinations with Special Emphasis on Epoxidation (of Carbamazepine)

Lack of Sister Chromatid Exchange Induction in Phenytoin‐Treated Patients with Epilepsy

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