(from OMIM) Epoxide hydrolases (EC 3.3.2.3 ) play an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons. Strickler et al. (1985) hypothesized a mutant form of microsomal epoxide hydrolase as the molecular basis for abnormal reactions to phenytoin and some other drugs. Phenytoin (diphenylhydantoin, dilantin) is metabolized by cytochrome P-450 monooxygenases to several oxidized products, including parahydroxylated and dihydrodiol metabolites. Arene oxides, which are reactive electrophilic compounds, are intermediates in these oxidative reactions. If not detoxified, arene oxide metabolites can covalently bind to cell macromolecules, resulting in cell death, mutation, tumors, birth defects, and, by acting as haptens, can lead to secondary immune phenomena.
References
Title: Epoxid hydrolase single gene polymorphism (RS1051740) and severity of chronic obstructive disease Antonova I, Gridnyev O, Galchinskaya V Ref: Wiad Lek, 75:2779, 2022 : PubMed
OBJECTIVE: The aim: The aim of the present study was to establish a link between polymorphic variants of the microsomal epoxide hydrolase gene and the severity of COPD in patients with COPD and coronary heart disease. PATIENTS AND METHODS: Materials and methods: The study included 128 patients with COPD and IHD, who were divided into two groups: group 1 included 72 patients with infrequent exacerbations of COPD (0-1 per year) and group 2 included 56 patients with frequent exacerbations of COPD (exacerbation of COPD <=2 per year). The control groups consisted of 15 smokers without COPD and IHD, 11 practically healthy non-smokers and 11 patients with IHD who do not smoke. All patients underwent DNA isolation and purification, followed by determination of the Tyr113His polymorphism of the EPHX1 microsomal epoxide hydrolase gene (rs1051740). RESULTS: Results: There was a significant association of the carriage of the CC genotype of the EPHX1 gene in patients with COPD and IHD (RO = 21.326 [95.0% CI 4.217-107.846], p <0.001) with a more severe course of COPD compared with the TT genotype of the EPHX1 gene. CONCLUSION: Conclusions: Patients with COPD and coronary heart disease who were carriers of a homozygous variant of the EPHX1 gene have a reliable association with a more severe course of COPD with frequent exacerbations (higher class according to GOLD classification and more severe symptoms of COPD according to the AT questionnaire).
Title: Fetal hydantoin syndrome with unilateral atypical cleft hand: additional evidence for vascular disruption De Smet L, Debeer P Ref: Genet Couns, 13:157, 2002 : PubMed
We report on 2 children of a mother treated with phenylhydantoine for post-surgical epilepsy. The hand malformation in one of them was indicative for a vascular disruption sequence.
Considering the role in the metabolism of chemicals played by biotransformation enzymes, we aimed at determining whether any association exists between genetic polymorphisms in CYP1A1, CYP2E1, epoxide hydrolase (EPHX), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to lymphomas. PCR-RFLP-based genotyping assays were used to determine the frequency of polymorphisms in CYP1A1 (3'-flanking region), CYP2E1 (5'-flanking region and intron 6), EPHX (exons 3 and 4), GSTM1 (deletion), GSTP1 (exon 5) and GSTT1 (deletion) in a case-control study comprised of 219 patients with morbus Hodgkin (MH) and non-Hodgkin's lymphomas (NHL) and 455 age- and sex-matched healthy individuals. The distribution of genotypes in CYP2E1-intron 6 was significantly different between the control group and all lymphomas (P = 0.03), patients with NHL (P = 0.024), and especially aggressive diffuse NHL (P = 0.007). Grading of NHL seemed to be associated with this polymorphism as well (P = 0.041). The EPHX-exon 3 genotype distribution was significantly different between control males and males with all lymphomas (P = 0.01) or with NHL (P = 0.019). The Val/Val genotype of GSTP1-exon 5 was prevalent in all MH [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.05-4.14] and this difference was particularly evident in females (OR = 2.97, 95% CI = 1.16-7.61). A significant difference in the distribution of GSTP1-exon 5 genotypes was found between NHL tumors >5 cm and those <5 cm (P = 0.03). The results suggest that genetic polymorphisms of biotransformation enzymes may play a significant role in the development of lymphoid malignancies.
OBJECTIVE Microsomal epoxide hydrolase is an important enzyme involved in the metabolism of endogenous and exogenous toxicants. Polymorphic variants of the human epoxide hydrolase gene vary in enzyme activity. We determined whether genetic variability in the gene encoding for microsomal epoxide hydrolase contributes to individual differences in susceptibility to the development of pre-eclampsia with or without the syndrome of Haemolysis, Elevated Liver enzymes, and Low Platelets (HELLP).
METHODS:
A total of 183 non-pregnant women with a history of pre-eclampsia, 96 of whom had concurrently developed the HELLP syndrome, and 151 healthy female controls were genotyped for the 113Tyr-->His polymorphism in exon 3 and the 139His-->Arg polymorphism in exon 4 of the epoxide hydrolase gene by a polymerase chain reaction-restriction fragment length polymorphism assay. Chi-square analysis was used for statistical evaluation of differences in polymorphic rates.
RESULTS:
In pre-eclampsia a higher frequency (29%) of the high activity genotype Tyr113 Tyr113 in exon 3 was found as compared to controls (16%, OR 2.0, 95% CI 1.2-3.7). There was no difference between groups for the 139His-->Arg polymorphism. In women with a history of pre-eclampsia, no difference in epoxide hydrolase genotypes was found between women who either did or did not develop the HELLP syndrome. In addition, a significant association was found between predicted EPHX activity and pre-eclampsia.
CONCLUSIONS:
Women with the high activity genotype in exon 3, which could reflect differences in metabolic activation of endogenous or exogenous toxic compounds, may have enhanced susceptibility to pre-eclampsia. However, polymorphisms in the epoxide hydrolase gene do not seem to influence the risk for concurrent development of the HELLP syndrome.
Microsomal epoxide hydrolase (mEH) is a conserved enzyme that is known to hydrolyze many drugs and carcinogens, and a few endogenous steroids and bile acids. mEH-null mice were produced and found to be fertile and have no phenotypic abnormalities thus indicating that mEH is not critical for reproduction and physiological homeostasis. mEH has also been implicated in participating in the metabolic activation of polycyclic aromatic hydrocarbon carcinogens. Embryonic fibroblast derived from the mEH-null mice were unable to produce the proximate carcinogenic metabolite of 7,12-dimethylbenz[a]anthracene (DMBA), a widely studied experimental prototype for the polycylic aromatic hydrocarbon class of chemical carcinogens. They were also resistant to DMBA-mediated toxicity. Using the two-stage initiation-promotion skin cancer bioassay, the mEH-null mice were found to be highly resistant to DMBA-induced carcinogenesis. In a complete carcinogenesis bioassay, the mEH mice were totally resistant to tumorigenesis. These data establish in an intact animal model that mEH is a key genetic determinant in DMBA carcinogenesis through its role in production of the ultimate carcinogenic metabolite of DMBA, the 3,4-diol-1,2-epoxide.
Title: Hand anomalies in fetal-hydantoin syndrome: from nail/phalangeal hypoplasia to unilateral acheiria Sabry MA, Farag TI Ref: American Journal of Medicine Genet, 62:410, 1996 : PubMed
Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.
Title: Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants Hassett C, Aicher L, Sidhu JS, Omiecinski CJ Ref: Hum Mol Genet, 3:421, 1994 : PubMed
Human microsomal epoxide hydrolase (mEH) is a biotransformation enzyme that metabolizes reactive epoxide intermediates to more water-soluble trans-dihydrodiol derivatives. We compared protein-coding sequences from six full-length human mEH DNA clones and assessed potential amino acid variation at seven positions. The prevalence of these variants was assessed in at least 37 unrelated individuals using polymerase chain reaction experiments. Only Tyr/His 113 (exon 3) and His/Arg 139 (exon 4) variants were observed. The genotype frequencies determined for residue 113 alleles indicate that this locus may not be in Hardy-Weinberg equilibrium, whereas frequencies observed for residue 139 alleles were similar to expected values. Nucleotide sequences coding for the variant amino acids were constructed in an mEH cDNA using site-directed mutagenesis, and each was expressed in vitro by transient transfection of COS-1 cells. Epoxide hydrolase mRNA level, catalytic activity, and immunoreactive protein were evaluated for each construct. The results of these analyses demonstrated relatively uniform levels of mEH RNA expression between the constructs. mEH enzymatic activity and immunoreactive protein were strongly correlated, indicating that mEH specific activity was similar for each variant. However, marked differences were noted in the relative amounts of immunoreactive protein and enzymatic activity resulting from the amino acid substitutions. These data suggest that common human mEH amino acid polymorphisms may alter enzymatic function, possibly by modifying protein stability.
Title: The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization Hassett C, Robinson KB, Beck NB, Omiecinski CJ Ref: Genomics, 23:433, 1994 : PubMed
Human microsomal epoxide hydrolase (mEH) is a xenobiotic-metabolizing enzyme that detoxifies reactive epoxides to more water soluble dihydrodiol compounds. We have isolated and sequenced clones that encode the entire human mEH gene (EPHX1). The primary nuclear transcript, extending from the start of transcription to the site of poly(A) addition, is 20,271 nucleotides in length. The human mEH gene contains 9 exons, separated by 8 introns; canonical intron/exon boundary sites are observed at each junction. The introns vary in size from 335 to 6696 bp and contain numerous repetitive DNA elements, including 18 Alu sequences (each > 100 nucleotides in length) within 4 introns. Alu sequences were classified with respect to subfamily assignment. Two thousand eighteen nucleotides 5' of the transcription start and 2501 nucleotides 3' of the poly(A) addition sites were also sequenced. To evaluate the human mEH promoter, chimeric constructs were prepared linking portions of the 5' mEH flanking sequence (up to -693 bp) to a CAT reporter gene, followed by transient transfection in both COS-1. and HepG2 cells. Results from these expression experiments suggest that the human mEH gene contains a weak core promoter and that inclusion of DNA sequences 5' of the minimal promoter region negatively regulates constitutive transcription.
PURPOSE: Therapy with anticonvulsants such as phenytoin, phenobarbital, and carbamazepine can be complicated by severe hypersensitivity reactions. Previous work has suggested that the predisposition to such reactions is based on an inherited abnormality in the detoxification of reactive metabolites of the drugs. However, there are no reports of familial occurrence of the reactions in the literature. In the current study, we examined a family in which three siblings developed hypersensitivity reactions to phenytoin, confirming the inheritance of a predisposition to the reactions. Detoxification of reactive metabolites of the anticonvulsants was studied in cells from the patients and their siblings. PATIENTS AND METHODS: Three siblings from a family of 12 siblings developed hypersensitivity reactions to phenytoin characterized by fever, rash, lymphadenopathy, and anicteric hepatitis. All recovered completely after discontinuation of treatment. One sibling tolerated phenobarbital without toxic sequelae. Peripheral blood mononuclear cells from the three patients and five additional siblings who had never taken anticonvulsants were exposed to oxidative metabolites of phenytoin, phenobarbital, and carbamazepine generated by a hepatic microsomal drug-metabolizing system in vitro. The toxicity of metabolites in the cells from the siblings was compared with that in cells from control subjects. RESULTS: Cells from each of the patients who had experienced a hypersensitivity reaction exhibited increased toxicity from metabolites of phenytoin and carbamazepine, while the cellular response to metabolites of phenobarbital was within normal limits. Cells from four of the other siblings showed an abnormal response to phenytoin metabolites, while cells from the final sibling detoxified phenytoin metabolites normally. CONCLUSION: Our observations on the patients confirm the inherited nature of phenytoin hypersensitivity reactions in vivo. In vitro studies demonstrated abnormal metabolite detoxification in the patients and several of their siblings. The detoxification defect included metabolites of phenytoin and carbamazepine but not of phenobarbital. A family history of a drug hypersensitivity reaction should alert physicians to the probability of a markedly increased risk of an adverse reaction in family members. In vitro assays to confirm adverse reaction risks may ultimately be able to provide individualized risk assessment for patients who must take anticonvulsants.
The well-known teratogenicity of several anticonvulsant medications is associated with an elevated level of oxidative metabolites that are normally eliminated by the enzyme epoxide hydrolase. In this study, we attempted to determine whether infants who are at risk for congenital malformations could be identified prenatally by the measurement of epoxide hydrolase activity. Before fetuses at risk could be identified, it was necessary to measure epoxide hydrolase activity in a randomly selected sample of amniocytes from 100 pregnant women. According to a thin-layer chromatographic assay, the randomly selected sample population had an apparently trimodal distribution, suggestive of an enzyme regulated by a single gene with two allelic forms. Fetuses homozygous for the recessive allele would have low epoxide hydrolase activity and would therefore be at risk if exposed to anticonvulsant drugs during gestation. In a prospective study of 19 pregnancies monitored by amniocentesis, an adverse outcome was predicted for four fetuses on the basis of low enzyme activity (less than 30 percent of the standard). In all four cases, the mother was receiving phenytoin monotherapy, and after birth the infants had clinical findings compatible with the fetal hydantoin syndrome. The 15 fetuses with enzyme activity above 30 percent of the standard were not considered to be at risk, and all 15 neonates lacked any characteristic features of the fetal hydantoin syndrome. These preliminary results suggest that this enzymatic biomarker may prove useful in determining which infants are at increased risk for congenital malformations induced by anticonvulsant drugs.
Title: Human microsomal xenobiotic epoxide hydrolase. Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization Skoda RC, Demierre A, McBride OW, Gonzalez FJ, Meyer UA Ref: Journal of Biological Chemistry, 263:1549, 1988 : PubMed
A lambda gt11 expression library constructed from human liver mRNA was screened with an antibody against human microsomal xenobiotic epoxide hydrolase. The clone pheh32 contains an insert of 1742 base pairs with an open reading frame coding for a protein of 455 amino acids with a calculated Mr of 52,956. The nucleotide sequence is 77% similar to the previously reported rat xenobiotic epoxide hydrolase cDNA sequence. The deduced amino acid sequence of the human epoxide hydrolase is 80% similar to the previously reported rabbit and 84% similar to the deduced rat protein sequence. The NH2-terminal amino acids deduced from the human xenobiotic epoxide hydrolase cDNA are identical to the published 19 NH2-terminal amino acids of the purified human xenobiotic epoxide hydrolase protein. Northern blot analysis revealed a single mRNA band of 1.8 kilobases. Southern blot analysis indicated that there is only one gene copy/haploid genome. The human xenobiotic epoxide hydrolase gene was assigned to the long arm of human chromosome 1. Several restriction fragment length polymorphisms were observed with the human epoxide hydrolase cDNA. pheh32 was expressed as enzymatically active protein in cultured monkey kidney cells (COS-1).
The mode of inheritance of insufficient phenytoin p-hydroxylation was studied in the family of a patient who had previously suffered from a phenytoin intoxication caused by insufficient metabolism of this drug. This family was compared with a control group. The rate of phenytoin metabolism was derived from the phenytoin/metabolite ratio in serum 6 hours after an oral test dose of 300 mg phenytoin. The propositus, a brother and a sister, were very slow metabolizers of phenytoin, with a metabolic ratio of approximately 20. In the other individuals, 22 family members of the second generation and 37 control subjects, a metabolic ratio of 4.7 +/- 2.2 (mean +/- SD; n = 59) was found. When comparing the members of the second generation (F2) with the control group, two statistically significantly different groups appear to exist: F2, with a metabolic ratio of 6.6 +/- 1.7 (mean +/- SD; n = 22), and the control group, with a metabolic ratio of 3.7 +/- 1.8 (mean +/- SD; n = 37) (p less than 0.001). Based on these results the mode of inheritance of this defect seems to be autosomal recessive.
Title: Possible prenatal hydantoin effect in a child born to a nonepileptic mother Chodirker BN, Chudley AE, Reed MH, Persaud TV Ref: American Journal of Medicine Genet, 27:373, 1987 : PubMed
We describe a child who was born with marked digital hypoplasia of his right hand. Although the mother was not an epileptic, the child was exposed in utero to diphenylhydantoin.
Title: Elevated glucocorticoid receptor levels in lymphocytes of children with the fetal hydantoin syndrome (FHS) Goldman AS, Van Dyke DC, Gupta C, Katsumata M Ref: American Journal of Medicine Genet, 28:607, 1987 : PubMed
Our recent studies of the teratogenic mechanisms of phenytoin (DPH) and glucocorticoids in mice have indicated that DPH utilizes the anti-inflammatory pathway of glucocorticoids in producing congenital defects, such as cleft palate. This pathway is influenced by H-2 and H-3 histocompatibility-linked genes in the mouse, such that congenic strains have H-2 or H-3 alleles that confer susceptibility to DPH-induced congenital defects, and susceptible H-2 congenic strains have high glucocorticoid receptor levels. However, other H-2 or H-3 alleles confer resistance to these defects in their otherwise genetically identical congenic partner strains, and "resistant" H-2 alleles are associated with low levels of these receptors. To determine whether this animal work is applicable to the human, we have sought to investigate whether the level of glucocorticoid receptors in circulating lymphocytes of children with the fetal hydantoin syndrome (FHS) is as it is in the animals. We found that children with FHS had glucocorticoid receptor levels significantly elevated above those of unaffected children with similar DPH exposure in control families. The receptor level of affected children was also significantly elevated above that of fathers of children with the FHS and of fathers and mothers of control children. These findings are consistent with those documented in the animal models and suggest that an elevated level of glucocorticoid receptors in lymphocytes may be a marker for susceptibility to the FHS syndrome.
Title: Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase Jackson MR, Craft JA, Burchell B Ref: Nucleic Acids Research, 15:7188, 1987 : PubMed
Title: Microsomal epoxide hydrolase activity in human x mouse hybrid cells Brown S, Chalmers DE Ref: Biochemical & Biophysical Research Communications, 137:775, 1986 : PubMed
Microsomal epoxide hydrolase (E.C.3.3.2.3) activity has been measured in human x mouse hybrid cells prepared from human cells expressing 6-7 x the activity of the mouse cells. Rabbit antihuman and antimouse antisera raised against purified enzymes were used to discriminate between human and mouse enzymes. All twenty five clones examined did not express human enzyme and this correlated with the loss of human chromosome 6 from each cell line. Four hybrids expressed 2-3 x the activity expressed by the mouse cell parent and these all retained more human chromosomes, specifically chromosome 19, than those with low activity. It is concluded that the human gene for epoxide hydrolase may be on chromosome 6 and that other gene products can affect the level of activity expressed by a cell.
To find out whether arene oxide metabolites of phenytoin and a genetic defect in arene oxide detoxification contribute to susceptibility to phenytoin-induced birth defects, lymphocytes from 24 children exposed to phenytoin throughout gestation and from their families were challenged in a blind protocol with phenytoin metabolites generated by a murine hepatic microsomal drug-metabolising system. 14 of the children had a "positive" assay result--ie, a significant increase in cell death associated with phenytoin metabolites. Each child with a positive result had one parent whose cells also were positive. A positive in-vitro challenge was highly correlated with major birth defects, including congenital heart disease, cleft lip/palate, microcephaly, and major genitourinary, eye, and limb defects. There was no difference between children with positive and negative results in the number or distribution of minor birth defects, including stigmata of the fetal hydantoin syndrome. Although many factors contribute to the outcome of pregnancies in epileptic women treated with phenytoin, a genetic defect in arene oxide detoxification seems to increase the risk of the baby having major birth defects.
A case history is presented of a patient who developed a severe phenytoin intoxication on a "therapeutic" dose of 300 mg/day. This phenomenon could be ascribed to a poor oxidative metabolizing capacity of this patient for phenytoin, as demonstrated by a low para-hydroxyphenyl-phenylhydantoin to phenytoin ratio in the urine. To characterize the specificity of this metabolic defect, debrisoquine and antipyrine oxidation were also studied. Contrary to expectations, this patient was shown to be an extensive debrisoquine metabolizer; the antipyrine clearance was even higher than normal. These findings suggest that phenytoin para-hydroxylation is regulated by an oxidative enzyme complex different from those which oxidize debrisoquine and antipyrine.
Title: Discordant expression of fetal hydantoin syndrome in a pair of dizygotic twins with different fathers. (Abstract) Phelan MC, Pellock JM, Nance WE Ref: American Journal of Human Genetics, 33:e67A, 1981 : PubMed
Arene oxide metabolites of phenytoin may be involved in the pathogenesis of drug-induced hepatotoxicity. We examined individual susceptibility to toxicity from such metabolites by exposing human lymphocytes to metabolites generated by a murine hepatic microsomal system. Cells from 17 controls showed no toxicity at concentrations of phenytoin from 31 to 125 microM. Cells from three patients with phenytoin hepatotoxicity manifested dose-dependent toxicity from the metabolites. Phenytoin alone was not toxic to cells. The patients' dose-response curves resembled the response of control cells in which epoxide hydrolase (a detoxification enzyme for arene oxides) was inhibited. Detoxification of non-arene oxide metabolites (e.g., of acetaminophen) was normal in patients' cells. Cells from parents of two patients had intermediate responses. Cells from a sibling of one patient showed no toxicity; a sibling of another patient had a response similar to that of the patient. A heritable defect in response to arene oxides thus may predispose some patients to phenytoin hepatotoxicity.
Title: Inheritance of phenytoin hypometabolism: a kinetic study of one family Vasko MR, Bell RD, Daly DD, Pippenger CE Ref: Clinical Pharmacology & Therapeutics, 27:96, 1980 : PubMed
Title: Pharmacogenetics: multiple interactions between genes and environment as determinants of drug response Vesell ES Ref: American Journal of Medicine, 66:183, 1979 : PubMed
Title: Inheritance of diphenylhydantoin hypometabolism: a pharmacokinetic study of one family. (Abstract) Vasko MR, Bell RD, Daly DD Ref: Clinical Pharmacology & Therapeutics, 21:120, 1977 : PubMed
Title: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW Ref: J Pediatr, 89:662, 1976 : PubMed
The fetal hydantoin syndrome is a variable pattern of altered growth and performance which includes unusual facies, distal phalangeal hyoplasia, and other defects occurring in some infants exposed in utero to hydantoins. A prospective study of 35 infants exposed prenatally to this class of anticonvulsants showed that 11% had sufficient features to be classified as having the fetal hydantoin syndrome. An additional 31% displayed some features compatible with the prenatal effects of hydantoins. A case-control study of 104 infants whose mothers received hydantoins during pregnancy supports these conclusions. Reduction of intellectual ability in infants with the fetal hydantoin syndrome is the area of greatest concern. Women being treated with hydantoin anticonvulsants should be told of the nature and magnitude of risks to the developing fetus before considering a pregnancy.
Title: Inhibition of diphenylhydantoin metabolism in rats and in rat liver microsomes by antitubercular drugs Kutt H, Verebely K, McDowell F Ref: Neurology, 18:706, 1968 : PubMed
Title: Insufficient Paraphydroxylation as a Cause of Diphenylhydantoin Toxicity Kutt H, Wolk M, Scherman R, McDowell F Ref: Neurology, 14:542, 1964 : PubMed
