Metabolic activation and covalent binding of phenytoin in the rat gingiva

Wortel, J. P.; Hefferren, John J.; Rao, G. Sasibhushana

doi:10.1111/j.1600-0765.1979.tb00789.x

Cited by 9 publications

(2 citation statements)

References 11 publications

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“…This biotransformation is thought to proceed via a 3,4-epoxide intermediate. This putative toxic metabolite has been implicated in the manifestation of a variety of adverse reactions to phenytoin, including teratogenicity (Martz et al, 1977), gingival hyperplasia (Wortel et al, 1979), and hepatotoxicity (Spielberg, 1986). The results obtained in the present study support the hypothesis that adverse reactions to phenytoin may arise as a consequence of the generation of chemically reactive epoxides by cytochrome P450 enzymes.…”

Section: Resultssupporting

confidence: 80%

Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

Riley

Kitteringham

Park

1989

Brit J Clinical Pharma

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The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism‐dependent toxicity of the latter is potentiated by pre‐treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase.

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Section: Resultssupporting

confidence: 80%

Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

Riley

Kitteringham

Park

1989

Brit J Clinical Pharma

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“…It is well recognized that in the body many drugs are converted to chemically reactive metabolites, which either uncouple integrated biochemical processes in the cell or covalently bind to macromolecules, such as proteins, lipids, and DNA, causing a variety of toxicities, including hypersensitivity reactions, cellular necrosis, and carcinogenesis [30,31]. These reactive metabolites have been identified as arene oxides in the case of drugs containing aromatic rings [32], and a good correlation has been observed between covalent binding of these metabolites to tissue proteins and drug-induced tissue adverse reactions [33].…”

Section: Discussionmentioning

confidence: 99%

Effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, major metabolites of phenytoin, on the occurrence of chronic-gingival hyperplasia: in vivo and in vitro study

Ieiri

Goto

Higuchi

et al. 1995

Eur J Clin Pharmacol

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The purpose of this study was to assess the possible role of the (R)- and (S)- enantiomers of the phenytoin metabolite p-HPPH in the pathogenesis of gingival hyperplasia (GH). About 98% of circulating p-HPPH is in the (S)-form. There were significant differences between patients with and without GH in (R)-p-HPPH level (0.055 vs 0.042 microgram.ml-1), both enantiomer/racemate level ratios, and R/S enantiomeric ratio (0.0313 vs 0.0232); an increase in serum (R)-p-HPPH level was observed in patients with GH. In separate experiments, the effect of p-HPPH enantiomers on the proliferation of the normal human dermal fibroblast was studied. The in vitro study showed that (R)-p-HPPH selectively stimulated fibroblast growth. The results suggest that the least abundant metabolite, (R)-p-HPPH, is the most toxic with respect to gingival hyperplasia.

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