Play all audios:
ABSTRACT A small percent of patients treated with phenytoin (DPH) develop hepatotoxicity. Covalent binding of arene oxide metabolites (AOM) of the drug to cell macromolecules could result in
cell death and secondary “hypersensitivity” reactions (fever, rash, eosinophilia). We tested the hypothesis that DPH hepatotoxicity results from decreased ability to detoxify AOM by
exposing lymphocytes to AOM generated by a murine hepatic microsomal system. Cells from 17 controls (including 3 patients chronically treated with DPH without side effects) exhibited no
toxicity (by trypan blue dye exclusion) over a DPH concentration range of 31-125 μM. When an inhibitor of epoxide hydrolase (TCPO) was added to the incubation, a dose-dependent increase in
cell death was noted. AOM of DPH are thus cytotoxic in the system. Cells from 3 patients who experienced DPH hepatotoxicity manifested damage in the absence of TCPO. Cells from both parents
of one patient, and the mother of a second showed an intermediate response. A sibling's cells had the same dose-response curve as one of the patients. All patients' cells showed
enhanced toxicity from mephenytoin, but a normal response to acetaminophen (metabolites of the latter are not AOM). DPH hepatotoxicity may be based on decreased ability to detoxify AOM, and
this appears to be a heritable trait. ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Johns Hopkins University School of Medicine, Depts. of Pediat. and Pharmacol., Div. of Clin.
Pharmacol., Baltimore, Maryland S P Spielberg, G B Gordon, P Goldstein & D A Blake Authors * S P Spielberg View author publications You can also search for this author inPubMed Google
Scholar * G B Gordon View author publications You can also search for this author inPubMed Google Scholar * P Goldstein View author publications You can also search for this author inPubMed
Google Scholar * D A Blake View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS
ARTICLE Spielberg, S., Gordon, G., Goldstein, P. _et al._ 374 PHARMACOGENETIC PREDISPOSITION TO PHENYTOIN HEPATO-TOXICITY ASSESSED IN VITRO. _Pediatr Res_ 15 (Suppl 4), 502 (1981).
https://doi.org/10.1203/00006450-198104001-00385 Download citation * Issue Date: 01 April 1981 * DOI: https://doi.org/10.1203/00006450-198104001-00385 SHARE THIS ARTICLE Anyone you share the
following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer
Nature SharedIt content-sharing initiative