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PubMed1993

Genetic polymorphism of alcohol and aldehyde dehydrogenase and the effects on alcohol metabolism.

Influence of genetic polymorphism at the alcohol dehydrogenase2 (ADH2) and aldehyde dehydrogenase2 (ALDH2) loci on ethanol elimination and blood acetaldehyde level was studied in healthy subjects. Polymorphic regions of the ADH2 and ALDH2 genes were amplified for genomic DNA by using the technique of polymerase chain reaction. The ADH2 genotype was determined by digestion with the restriction enzyme MaeIII and the ALDH2 genotype was defined by hybridization with sequence specific oligonucleotide probes. Both loci were typed for unrelated 58 individuals by using the above methods. The gene frequencies of each locus were estimated as follows; 0.31 and 0.69 for ADH2*1 and ADH2*2, respectively, and 0.73 and 0.27 for ALDH2*1 and ALDH2*2, respectively. These values were consistent with the Hardy-Weinberg equilibrium. Pedigree analysis of 6 families with 46 subjects on both loci confirmed Mendelian inheritance. In order to investigate differences in ethanol elimination among ADH2 and ALDH2 genotype groups, 0.4 g/kg body weight of ethanol was administered to 93 subjects whose genotypes of both loci were determined by the above methods and blood ethanol and acetaldehyde levels were measured. None of the subjects homozygous for the ALDH2*1 allele showed facial flushing and any increase in blood acetaldehyde level. All the homozygotes and heterozygotes with the ALDH2*2 allele exhibited facial flushing, and the former showed a marked increase in blood acetaldehyde level and the latter did a mild increase. On the other hand, the influence of the ADH2 genotype on blood acetaldehyde level was not significant. The values of Widmark's beta 60 (mg/ml/hr) and ethanol elimination rate (mg/kg/hr) showed significant differences among the three groups of the ALDH2 genotypes in each group of the three ADH2 genotypes, and in decreasing order of both the values were ALDH 2*1/*1, ALDH2*1/*2, ALDH2*/*2, However, there were no significant differences in the values among the ADH2 genotypes.

Acetaldehyde↗

PubMed1997

A study of apolipoprotein A-IV genetic polymorphism, serum lipids and lipoproteins in Beijing habitants.

OBJECTIVES: Apolipoprotein (apo) A-IV genetic polymorphism and its effect on serum lipids, apoA-I and apoA-IV were investigated in order to clarify the role of apoA-IV gene during the development of hyperlipidemia. METHODS: Four polymorphic sites (codon 127, 167, 347 and 360) of apoA-IV gene (exon 3) were determined in two groups of inhabitants in Beijing (Group I: 145 healthy individuals; Group II: 41 cases of hyperlipidemic patients and controls) by PCR-RFLP technique. Serum concentrations of HDL-cholesterol (HDL-C), HDL3-C, HDL2-C, triglyceride (TG), total cholesterol (TC), apoA-I and apoA-IV were studied among the individuals with different genotypes of apoA-IV. RESULTS: In Group I, frequencies of the alleles were 0.648 and 0.352 in codon 127; 0.972 and 0.028 in codon 167; 0.817 and 0.183 in codon 347. Two common alleles were 0.941 and 0.059 in codon 360. The results indicated that cases of codon 127 heterozygotes had a significantly higher serum TC level and cases of apoA-IV Ser127 homozygotes kept a markedly low TG level. Both homozygotes and heterozygotes which carried apoA-IV His 360 exhibited a significantly higher concentration of TC in comparing with that of apoA-IV Gln 360 homozygotes. The data from Group II showed that the allele frequency of His 360 had a significant difference between patients and controls. CONCLUSIONS: Certain polymorphic sites of apoA-IV gene might influence the serum lipid levels in both healthy persons and hyperlipidemic patients. His 360 polymorphic position might have a relationship with the development of hyperlipidemia.

Adult↗

PubMed2006

Identification of a novel mutation and a genetic polymorphism of EVER1 gene in two families with epidermodysplasia verruciformis.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare autosomal recessive disease. The main clinical features include three kinds of lesions, high risk of skin cancer, and abnormal susceptibility to HPV 5 and 8. Recent studies have shown that mutations in EVER1 and EVER2 genes are responsible for the condition. OBJECTIVE: In the present study, we investigated the molecular basis of EV in two families with EV. METHODS: PCR and direct sequencing of the EVER1 and EVER2 genes were used to identify and confirm the mutations in our probands in the two families. Direct sequencing and SacI digestion were used to detect the polymorphism of exon 6. RESULTS: Sequencing of the EVER1 and EVER2 genes revealed a novel mutation and a genetic polymorphism. The novel mutation by inserting CATGT after nucleotide 916 in exon 9 resulted in a nonsense mutation and a premature termination codon. Direct sequencing and SacI digestion revealed genotype frequencies of C457T, 457T, and 457C alleles in 16 individuals of EV families were of 9, 3, and 4, which were 26, 0, and 24 in 50 unrelated normal controls, respectively. To our knowledge, the novel mutation and genetic polymorphism have not been described in literatures. CONCLUSIONS: The growing number of mutations in EV pedigrees supports the hypothesis that EVER1 and EVER2 are the molecular basis of EV.

Adult↗

PubMed2006

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach.

OBJECTIVE: To clarify the effect of genetic polymorphism of CYP2C19 on pharmacokinetics of phenytoin and phenobarbital using a Non-linear Mixed Effects Modelling analysis in Japanese epileptic patients. METHOD: A total of 326 serum phenytoin concentrations were collected from 132 patients, and a total of 144 serum phenobarbital concentrations were collected from 74 patients during their clinical routine care. RESULT: The maximal elimination rate of phenytoin decreased by 10.2% in patients with CYP2C19*1/*2 compared with patients with normal CYP2C19. The Michaelis-Menten constants in the patients with CYP2C19*1/*3 and the poor metabolizers of (CYP2C19*2/*2 or *2/*3 or *3/*3) were 27% and 54% higher than those for the patients with normal CYP2C19, respectively. The total body clearance of phenobarbital decreased by 19.3% in patients with CYP2C19*1/*3 or the poor metabolizers of CYP2C19 compared with patients with normal CYP2C19 or with CYP2C19*1/*2. CONCLUSION: These findings indicated that the genetic polymorphisms of CYP2C19 contribute to the pharmacokinetic variability of phenytoin and phenobarbital, the poor metabolizers of CYP2C19, which are relatively common in Asian groups.

Adult↗

PubMed2001

Cytochrome P450 2E1 genetic polymorphism and gastric cancer in Changle, Fujian Province.

AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2E1 polymorphisms are associated with risks of gastric cancer. METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including demographic characteristics, diet intake, and alcohol and tobacco consumption of individuals in our study were completed by a standardized questionnaire.PCR-RFLP revealed three genotypes:heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1. RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 individuals in gastric cancer group(6.6%), whereas there was only one in the control group (1.1%). However, there was no statistically significant difference between the two groups (two-tailed Fisher's exact test P=0.066). Individuals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR=1.50) and C2/C2 (OR=7.34) than individuals in control group (chi(2) =4.597, for trend P=0.032). The frequencies of genotypes with the C2 allele (C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele (C1/C1 genotype) among individuals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that individuals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer. CONCLUSION: Polymorphism of CYP2E1 gene may have some effect in the development of gastric cancer in Changle county, Fujian Province.

Aged↗

PubMed2003

Frequency of MRP1 genetic polymorphisms and their functional significance in Caucasians: detection of a novel mutation G816A in the human MRP1 gene.

OBJECTIVE: The aim of the present study was to determine the frequency of the G816A, T825C, T1684C, and G4002A genetic polymorphisms of the human MRP1 gene in 230 healthy Caucasians. The functional assessment of these mutations was performed in fluorescence-activated cell sorting (FACS)-sorted peripheral blood CD4+ cells in a further 61 healthy volunteers by determining MRP1 mRNA expression. METHODS: Genotyping of the MRP1 was carried out using real-time polymerase chain reaction (PCR) assays. Quantitative determination of the MRP1 mRNA expression was performed with real-time reverse-transcription-PCR. RESULTS: A novel silent mutation G816A in exon 8 was found in this study. Allele frequencies of the 816A, 825C, 1684C, and 4002A were 4.1, 30.0, 80.0, and 28.3%, respectively. The frequency of the T825C polymorphism was comparable with that found in a previous Japanese study. In contrast, the frequency of the T1684C (OR 0.06, 95% CI 0.03-0.11, P<0.0001, vs Japanese) and the G4002A (OR 0.47, 95% CI 0.24-0.86, P=0.01, vs Japanese) was significantly rarer. The mean MRP1 mRNA expression in peripheral blood CD4+ cells was 1.03x10(4) +/- 3.8x10(3) molecules/ng of total RNA with an eightfold variation among individuals. However, MRP1 mRNA expression in CD4+ cells was not found to correlate with genetic polymorphisms investigated in this study. CONCLUSIONS: The genotypic results observed show an ethnic difference in the frequencies of the MRP1 genetic polymorphisms between Japanese and Caucasians. Further studies are required to better understand the clinical consequences of the MRP1 genetic variants.

Adult↗

PubMed2004

[Genetic polymorphism of cytomegalovirus strains responsible of congenital infections].

OBJECTIVES: Congenital Cytomegalovirus (CMV) infection is the main cause of neurological handicap in young children. The objective for studying genetic polymorphism of strains responsible for congenital infection is to identify CMV strains or groups of strains which would be more frequent in this context and/or which would be responsible for more severe congenital infection. METHODS: In this paper, we report and analyze the literature concerning the genetic polymorphism of CMV strains responsible of congenital infection, in the genes coding for the envelop protein B and the non structural UL144 protein and in the CMV short tandem repeats. RESULTS AND CONCLUSION: All UL144 and gB genotypes can be vertically transmitted from mothers to fetuses, none of these studies has shown any link between the genotypes and the severity of congenital disease. Moreover, no link between short tandem repeats polymorphism and severity of congenital disease has been demonstrated. However, short tandem repeats analysis may be a powerful tool to study the epidemiology of CMV congenital infections.

Cytomegalovirus↗

PubMed2006

Effects of arsenic exposure and genetic polymorphisms of p53, glutathione S-transferase M1, T1, and P1 on the risk of carotid atherosclerosis in Taiwan.

To evaluate the joint effects between genetic polymorphisms of glutathione S-transferase M1, T1, P1, and p53, and arsenic exposure through drinking well water on the risk of carotid atherosclerosis, 605 residents including 289 men and 316 women were recruited from a northeastern area of Taiwan. Carotid atherosclerosis was diagnosed by either a carotid artery intima-media thickness (IMT) of >1.0 mm, a plaque score of > or =1, or stenosis of >50%. A significant age- and gender-adjusted odds ratio of 3.3 for the development of carotid atherosclerosis was observed among the high-arsenic exposure group who drank well water containing arsenic at levels >50 microg/L. The high-arsenic exposure group with GSTP1 variant genotypes of Ile/Val and Val/Val, and with the p53 variant genotypes of Arg/Pro and Pro/Pro had 6.0- and 3.1-fold higher risks of carotid atherosclerosis, respectively. In addition, the high-arsenic exposure group with one or two variant genotypes of GSTP1 and p53 had 2.8- and 6.1-fold higher risks of carotid atherosclerosis, respectively, and showed a dose-dependent relationship. A multivariate-adjusted odds ratio of 3.4 for the risk of carotid atherosclerosis among study subjects with the two variant genotypes of GSTP1 and p53 was also found. Our study showed the joint effects on the risk of carotid atherosclerosis between the genetic polymorphisms of GSTP1 and p53, and arsenic exposure.

Age Factors↗

PubMed2006

Evidence for a functional genetic polymorphism of the human retinoic acid-metabolizing enzyme CYP26A1, an enzyme that may be involved in spina bifida.

BACKGROUND: CYP26A1, together with CYP26B1 and CYP26C1, are key enzymes of all-trans retinoic acid (RA) inactivation and their specific and restricted expression in developing embryos participate in the fine tuning RA levels. As RA is a critical regulator of gene expression during embryonic development, the imbalance between the synthesis and degradation of RA during embryogenesis could contribute to malformations and developmental defects. METHODS: A PCR-single strand conformation polymorphism (PCR-SSCP) strategy was developed to screen for CYP26A1 sequence variations that could affect the enzyme expression and/or activity and applied to DNA samples from 80 unrelated Caucasians, comprising 40 French healthy volunteers and 40 Italian patients with spina bifida. The consequence of the 1-bp deletion identified in the coding sequence was investigated by an in vitro functional assay using COS-7 cells. RESULTS: A total of 7 polymorphisms were identified, comprising 1 nucleotide deletion in the coding sequence (g.3116delT) that results in a frameshift and consequently in the creation of a premature stop codon. The g.3116delT mutation is of particular interest because it was identified in a patient with spina bifida and likely encodes a truncated protein with no enzymatic activity, as demonstrated by our preliminary in vitro data. CONCLUSIONS: Despite the fact that our findings could not show any evidence that the CYP26A1 genetic polymorphism has implications in the pathogenesis of spina bifida, this work represents the first description of a functional genetic polymorphism affecting the coding sequence of the human CYP26A1 gene.

Animals↗

PubMed2003

Genetic polymorphisms and prostate cancer risk.

The identification of common genetic polymorphisms that influence susceptibility to PC would allow an early risk assessment with earlier and therefore potentially more effective intervention by chemopreventive means. In this review we focus on published case-control studies and meta-analyses of the following polymorphic genes that may play a role in etiology of the androgen receptor (AR), the prostate-specific antigen (PSA), 5alpha-reductase type II gene (SRD5A2), cytochrome P450c17alpha (CYP17), cytochrome P4503A4 (CYP3A4) and a putative hereditary PC susceptibility gene, ELAC2.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1998

Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1.

Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer.

Adult↗

PubMed2002

Genetic polymorphism of antithrombin III, haptoglobin, and haemopexin in wild and domestic European rabbits.

Genetic polymorphism of European rabbit (Oryctolagus cuniculus) plasma proteins antithrombin III, haptoglobin, and haemopexin was investigated by means of isoelectric focusing in free and immobilized pH gradients followed by immunoblotting. The study of two wild and one domestic populations led to the recognition of six alleles of antithrombin III and haptoglobin, and five alleles of haemopexin.

Animals↗

PubMed2004

[Associations between genetic polymorphisms of glutathione S-transferase M1 and T1, smoking and susceptibility to colorectal cancer: a case-control study].

OBJECTIVE: To evaluate the associations between genetic polymorphisms of glutathione S-transferase M1 and T1 (GSTM1 and GSTT1), smoking and susceptibility to colorectal cancer. METHODS: A case-control study of 126 patients and 343 healthy controls was conducted to investigate the role of GSTM1 and GSTT1 polymorphisms in colorectal cancer. Genotypes of GSTM1 and GSTT1 polymorphisms were analyzed by multiplex allele-specific polymerase chain reaction (PCR). RESULTS: The frequencies of GSTM1 null and GSTT1 null genotypes were 55.5% and 20.4%, respectively. After adjustment for age and sex, among those with GSTT1 null genotype, the GSTM1 null genotype had a significant increased risk of rectal cancers compared to GSTM1 non-null genotype (OR=9.74, 95% CI, 1.13 - 83.85). A 2.22-fold risk of colon cancers was associated with GSTM1 null genotype compared to GSTM1 non-null genotype among current smokers (P >0.05). Individuals with GSTT1 null genotype and currently smoking had a significant risk of colon cancers (OR = 4.55, 95% CI, 1.14 - 18.17), and rectal cancers (OR = 4.60, 95% CI, 1.11 - 19.11). CONCLUSION: This study suggests that certain null GSTM1 and GSTT1 genotypes may be associated with an elevated risk of colorectal cancer which may be modified by interaction of the two genetic polymorphisms and cigarette smoking.

Adult↗

PubMed2005

Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population.

Glucocorticoid receptor, encoded by NR3C1, is a transcriptional regulator of many drug metabolizing enzymes and anti-inflammatory molecules. In order to identify genetic variations of the NR3C1 gene, genomic DNA from 265 Japanese individuals was sequenced. Fifty genetic polymorphisms were identified, including 32 novel ones [3 were in coding exons, 17 in the introns, 4 in the 5'-untranslated region (UTR), and 8 in the 5'-flanking region]. The novel nonsynonymous variation was 420G>T (Lys140Asn), and the allele frequency was 0.004. We did not detect any nonsynonymous polymorphism reported previously in other races, including a relatively frequent SNP Asn363Ser found in Caucasians and African-Americans. Thus, ethnic differences between Japanese and other races are suggested to exist in NR3C1.

Amino Acid Substitution↗

PubMed2005

Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction.

OBJECTIVES: This study sought to evaluate the effect of genetic polymorphism G894T on endothelial nitric oxide synthase (eNOS); on the risk for myocardial infarction (MI); and on the release of von Willebrand factor (vWF), interleukin (IL)-6, IL-1b, and oxidized low-density lipoprotein (ox-LDL) levels during the acute phase of MI and one year after the event. BACKGROUND: Genetic polymorphism G894T on eNOS has been associated with increased cardiovascular risk. However, its role during the acute phase of MI is unknown. METHODS: The study population consisted of 228 patients with a first event of premature MI and 519 matched control patients. One year after the event, 61 patients and 205 control patients were recalled for the follow-up study. Blood sampling was performed during the acute phase and after one year. RESULTS: The risk for MI in 894TT was 1.992 (95% confidence interval [CI], 1.131 to 3.485), p < 0.05 versus GG+GT; 2.038 (95% CI, 1.125 to 3.695), p < 0.05 versus GG; and 2.009 (95% CI, 1.106 to 3.651), p < 0.05 versus GT. During the acute phase, vWF was higher in GT+TT (121.02 +/- 5.47%) versus GG (84.6 +/- 7.1%, p < 0.01), an effect persisting after one year (90.4 +/- 3.8 vs. 73.1 +/- 4.6%, p < 0.01). During the acute phase, GT+TT had higher ox-LDL and IL-6 (131.2 +/- 6.4 IU/l and 8.5 +/- 0.7 pg/ml) compared with GG (101.7 +/- 9.64 IU/l and 6.2 +/- 0.8 pg/ml, p < 0.05 for both), but no difference was found at one year. CONCLUSIONS: G894T polymorphism on the eNOS gene increases the risk for premature MI and modifies the response of vascular endothelium during the acute phase of MI by affecting the release of vWF, IL-6, and oxidative stress status, an effect diminished one year after the event.

Female↗

PubMed2006

Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans.

P-glycoprotein (PGP) is a polymorphic transporter encoded by the ABCB1 gene that contributes to the access of xenobiotics into the brain. There is no report on associations between genetic polymorphisms in ABCB1 and the clinical effects of fentanyl, although fentanyl may be a substrate of PGP. One hundred and twenty-six (126) unrelated Korean patients under spinal anesthesia with intravenous fentanyl (2.5 microg/kg) were recruited. Clinical effects (bispectral index, respiration rate, and need for oxygen supplementation) were monitored and these were compared between genotypes for three single nucleotide polymorphisms in ABCB1 (1236C>T, 2677G>T/A, and 3435C>T). The allele and genotype frequencies were similar to previous data from Asians; the three major haplotypes, TTT (30%), TGC (24%), and CGC (24%) were expected among nine known haplotypes. During the initial 10 min, there were differences in suppression of respiration rate by fentanyl among the three genotypes (P=0.0933 for 1236C>T; P=0.0941 for 2677G>A/T; P=0.0013 for 3435C>T, repeated-measures analysis of variance), but the differences in bispectral index among genotypes were not observed. Furthermore, patients carrying the linked 3435T and 2677T alleles showed a significant difference in the level of respiratory suppression (P=0.0056); those with genotypes susceptible to fentanyl (1236TT, 2677TT, and 3435TT) showed early (2-3 min) and profound suppression of respiration (65-73% of initial respiration rate) compared with other resistant genotypes (83-85% of initial respiration rate in 1236CC, 2677GG, and 3435CC). Although the need to supply oxygen was not significantly different between genotypes, there was a trend for increased demand by patients carrying both 1236T and 3435T alleles (P=0.0847). In conclusion, our results confirm ABCB1 genotype data for Koreans and suggest that analysis of ABCB1 polymorphisms may have clinical relevance to prevent respiratory suppression by intravenous fentanyl or to anticipate its clinical effects.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1987

Tracheal mucociliary transport in laboratory mice: evidence for genetic polymorphism.

Mean tracheal transport velocities of inhaled 3 mu coumarin-bound monodisperse latex spheres, measured by epi-fluorescence through the intact trachea of anesthetized mice, were 2.29 +/- 0.52 mm/min for C57BL/6J, 0.40 +/- 0.42 mm/min for DBA/2J mice and 1.47 +/- 0.87 mm/min for (C57BL/6J X DBA/2J) F1 mice. A nonparametric analysis of the observed proportions of mice expressing parental phenotypes in second filial, two first backcross and one second backcross generations confirmed the polymorphism to be genetically determined and consistent with a single-locus mode of inheritance.

Animals↗

PubMed1987

Genetic polymorphism of human cytochrome P-450 (S)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P-450 isozyme as cause of the genetic deficiency.

The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2-5% of Caucasians and 18-23% of Japanese subjects a specific cytochrome P-450 isozyme, P-450 meph, is functionally deficient or missing. We have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephenytoin hydroxylation polymorphism. This is demonstrated by immunoinhibition and immunoprecipitation of microsomal (S)-mephenytoin 4-hydroxylation activity and by the recognition by anti-LKM2 antibodies of a single protein band on immunoblots of human liver microsomes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis or isoelectric focusing. The cytochrome P-450 recognized by anti-LKM2 antibodies was immunopurified from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of (S)-mephenytoin. Comparison of the EM-type cytochrome P-450 to that isolated from PM livers revealed no difference in regard to immuno-cross-reactivity, molecular weight, isoelectric point, relative content in microsomes, two-dimensional tryptic peptide maps, one-dimensional peptide maps with three proteases, amino acid composition, and amino-terminal protein sequence. Finally, the same protein was precipitated from microsomes prepared from the liver biopsy of a subject phenotyped in vivo as a poor metabolizer of mephenytoin. These data strongly suggest that the mephenytoin hydroxylation deficiency is caused by a minor structural change leading to a functionally altered cytochrome P-450 isozyme.

Aryl Hydrocarbon Hydroxylases↗