Biomedical subjects

N He

Publications and source records attributed to N He.

At least 37 records · Page 2Linked to original sources

PubMed1999

Dextromethorphan O-demethylation polymorphism in an African-American population.

OBJECTIVE: One hundred eighty-one (97 F, 84 M) unrelated healthy African-American subjects (aged 18-41 years) were phenotyped based on their dextromethorphan (DMP) O-demethylation ability. METHODS: Each subject was given 15 mg DMP orally and collected 8-h urine. The concentrations of DMP and its metabolite dextrophan (DOP) were determined by HPLC with ultraviolet detection. Metabolic ratio (MR) was expressed as the ratio of DMP to DOP molar amount in urine. RESULTS: The frequency distribution histogram of the MR was bimodal, and probit analysis of this frequency gave an antimode value of 0.34. Seven subjects [3.9%, 95% confidence interval (CI) 1.1%-6.7%] were classified as poor metabolizers (PMs). CONCLUSION: This deficient frequency is in complete agreement with the reported ones in two smaller investigations in the African-American populations.

Adolescent↗

PubMed1999

Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects.

OBJECTIVE: To determine whether the gene dosage of CYP2C19 affects the metabolism of diazepam and desmethyldiazepam in healthy Chinese subjects. SUBJECTS AND METHODS: Eighteen unrelated adult men were recruited for the study from a total of 101 healthy Chinese volunteers who had been screened for CYP2C19 phenotype and genotype. All subjects received a single oral dose (5 mg) of diazepam, and the pharmacokinetics of diazepam and desmethyldiazepam were compared in six ml homozygotes (ml/ml), six ml heterozygotes (wt/ml), and six wild-type homozygotes (wt/wt). RESULTS: The plasma elimination half-life values of diazepam (84.0 +/- 13.7 hours) and desmethyldiazepam (176.0 +/- 28.9 hours) in subjects of ml/ml were significantly longer than those (62.9 +/- 9.8 hours for diazepam; 132.1 +/- 24.9 hours for desmethyldiazepam; both P < .01) in subjects of wt/ml or those (20.0 +/- 10.8 hours for diazepam; 99.2.+/- 21.7 hours for desmethyldiazepam; both P < .01) in subjects of wt/wt. A significant difference in the corresponding half-life values existed between the wt/ml and wt/wt subjects (P < .01). As expected, the slowest mean clearance of diazepam was observed in the ml/ml subjects (2.8 +/- 0.9 mL/min) and the fastest in the wt/wt subjects (19.5 +/- 9.8 mL/min), with the wt/ml heterozygotes having an intermediate value (7.2 +/- 2.6 mL/min). CONCLUSION: The presence of a single-nucleotide polymorphism (G681A) of the CYP2C19 gene cosegregates with the impaired metabolism of diazepam and desmethyldiazepam among Chinese subjects in a gene-dosage effect manner.

Adult↗

PubMed1999

Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes.

AIMS: The present study was designed to define the kinetic behaviour of sertraline N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P450 involved in this metabolic pathway. METHODS: The kinetics of the formation of N-demethylsertraline were determined in human liver microsomes from six genotyped CYP2C19 extensive (EM) and three poor metabolisers (PM). Selective inhibitors of and specific monoclonal antibodies to various cytochrome P450 isoforms were also employed. RESULTS: The kinetics of N-demethylsertraline formation in all EM liver microsomes were fitted by a two-enzyme Michaelis-Menten equation, whereas the kinetics in all PM liver microsomes were best described by a single-enzyme Michaelis-Menten equation similar to the low-affinity component found in EM microsomes. Mean apparent Km values for the high-and low-affinity components were 1.9 and 88 microm and V max values were 33 and 554 pmol min-1 mg-1 protein, respectively, in the EM liver microsomes. Omeprazole (a CYP2C19 substrate) at high concentrations and sulphaphenazole (a selective inhibitor of CYP2C9) substantially inhibited N-demethylsertraline formation. Of five monoclonal antibodies to various cytochrome P450 forms tested, only anti-CYP2C8/9/19 had any inhibitory effect on this reaction. The inhibition of sertraline N-demethylation by anti-CYP2C8/9/19 was greater in EM livers than in PM livers at both low and high substrate concentrations. However, anti-CYP2C8/9/19 did not abolish the formation of N-demethylsertraline in the microsomes from any of the livers. CONCLUSIONS: The polymorphic enzyme CYP2C19 catalyses the high-affinity N-demethylation of sertraline, while CYP2C9 is one of the low-affinity components of this metabolic pathway.

Antibodies, Monoclonal↗

PubMed1999

Cocaine induces cell death within the primate fetal cerebral wall.

Transferase dUTP nick-end labelling (TUNEL) analysis was used to compare the occurrence of cell death in the cerebral wall of cocaine-exposed and drug-naïve monkey fetuses. The rhesus monkeys providing the drug-exposed fetuses received 10 mg/kg of cocaine orally (in fruit treats) in the morning and in the evening between pregnancy days 50 and 65. The control pregnant animals received fruit treats only. The fetuses were removed for analysis by Caesarean section 10 h after the last cocaine treatment. The sections of the cerebral wall from the cocaine-exposed fetuses contained significantly higher numbers of TUNEL-positive nuclei (counted either per section area or per 1000 unlabeled nuclei) than the matching sections from the drug-naïve fetuses. This elevation in the number of TUNEL-positive cells was observed through the entire depth of the fetal cerebral wall including its proliferative and intermediate zones, cortical plate and the marginal zone. The present study demonstrates that consumption of cocaine during pregnancy can result in increased occurrence of cell death in the developing cerebrum.

Animals↗

PubMed1999

Differential attrition rates and active parental consent.

Active parental consent in survey research poses ethical and practical concerns. One common argument against the requirement of active consent procedures is its effect on participation rates. There is additional concern that higher risk groups may be underrepresented in the final sample. Empirical support of differential attrition, however, is lacking. In the current multisite longitudinal study, passive consent procedures were approved for the collection of pretest data. For subsequent years of data collection, active parental consent procedures were required. In this article, we use the pretest data to examine demographic, attitudinal, and behavioral differences between those students for whom active consent was provided and those for whom active consent was either denied or for whom no response was received. The results indicate that active consent procedures produce deleterious effects on participation rates and lead to an underrepresentation of at-risk youth in the sample.

Adolescent↗

PubMed1999

Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease.

An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is the focal and sporadic formation of renal and extrarenal cysts. Recent documentation of somatic PKD1 mutations in cystic epithelia of patients with germ-line PKD1 mutations suggests a "two-hit" model for cystogenesis in type 1 ADPKD. This study tests whether the same mechanism for cystogenesis might also occur in type 2 ADPKD. Genomic DNA was obtained from 54 kidney and liver cysts from three patients with known germ-line PKD2 mutations, using procedures that minimize contamination of cells from noncystic tissue. Using intragenic and microsatellite markers, these cyst samples were screened for loss of heterozygosity. The same samples were also screened for somatic mutations in five of the 15 exons in PKD2 by single-stranded conformational polymorphism analysis. Loss of heterozygosity was found in five cysts, and unique intragenic mutations were found in seven other cysts. In 11 of these 12 cysts, it was also determined that the somatic mutation occurred nonrandomly in the copy of PKD2 inherited from the unaffected parent. These findings support the "two-hit" model as a unified mechanism for cystogenesis in ADPKD. In this model, the requirement of a somatic mutation as the rate-limiting step for individual cyst formation has potential therapeutic implications.

Base Sequence↗

PubMed1999

Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.

There are ethnic differences in the prevalence and severity of hypertension and asthma and in beta-2 adrenergic receptor (BAR2)-mediated vascular responses. Two common polymorphisms of the human BAR2, Arg16 to Gly and Gln27 to Glu, are associated with alterations in BAR2 response, both in vitro and in vivo. Ethnic differences in disease manifestations and responses to treatment may be explained by the altered frequency of BAR2 polymorphisms. To determine the relative frequencies of the Arg16 to Gly and Gln27 to Glu BAR2 polymorphisms in different ethnic groups we studied 415 (123 African-American, 188 Caucasian-American and 104 Chinese) healthy individuals. There was a marked interethnic difference in the frequency of the BAR2 polymorphisms among the ethnic groups. The Glu27 allele was more frequent in Caucasian-American (34.8%) than in African-American individuals (20.7%) (P = 0.0001) and much less frequent in Chinese individuals (7.2%) (P = 0.0001 versus African-American or Caucasian-American). The homozygous Glu27 genotype was more frequent in Caucasian-American (15.4%) than African-American individuals (4.9%) (P = 0.003) and was not observed in Chinese. The Gly16 allele (54.3% versus 41.3%) and homozygous genotype (35.1% versus 18.3%) were more common in Caucasian-American than Chinese individuals (P = 0.003 for both). There is a marked ethnic difference in the frequency of these two common BAR2 polymorphisms among African-American, Caucasian-American and Chinese individuals, with a markedly reduced frequency of the Glu27 polymorphism, the polymorphism associated with resistance to desensitization and increased BAR2 responses, in African-American and Chinese individuals. Such ethnic genotypic differences may explain previously observed alterations in the response to the BAR agonists in different ethnic groups.

Black or African American↗

PubMed1999

Hepatic radioembolization with Yttrium-90 glass microspheres for treatment of primary liver cancer.

OBJECTIVE: To study the clinical results of hepatic radioembolization with Yttrium-90 (90Y) glass microspheres in the treatment of primary liver cancer. METHODS: Seventeen patients with liver cancer were treated with glass microspheres from August 1996 to May 1998. Hepatic radioembolization with 90Y and lipiodol-ultrafluid was used. Percutaneous port-catheter system (PCS) implantations via femoral artery were performed in 12 patients. RESULTS: In the 17 patients, their mean ratio of absorbed doses between tumor and normal liver was 2.4:1. CT showed a significant reduction in tumor size in 11 of the 17 patients. Average survival was 19.5 months. The indwelling catheters of all the 12 patients were patent and no catheter tip locations were found. CONCLUSIONS: 90Y glass microsphere is one of the best radioisotopes. Not only good responses to the therapy of 90Y glass microspheres can be achieved in patients with metastatic liver cancer, but also in those with primary liver cancer, specially the localized or hypervascular mass. The patients with massive arterioportal shunt should not be limited to this form of radiation therapy. The percutaneous PCS implantation via the femoral artery is a new passageway for the treatment of primary liver cancer with 90Y glass microspheres and other interventional therapy.

Adult↗

PubMed1999

Effect of immunization in mice with recombinant DNA encoding the hepatitis C virus structural protein.

OBJECTIVE: To explore the possibility and the efficacy of immune responses in mice inoculated with recombinant plasmid pCD-HCV1 and to lay a foundation for HCV nucleic acid vaccine development in the future. METHODS: The gene fragment coding C and E regions of HCV-II (type I b) was inserted into pCD-SR alpha 1 expression vector and formed pCD-HCV1 and then was injected into quadriceps muscles of Balb/c mouse. Serum anti-HCV level of mice was tested by ELISA (A value). Spleen cells proliferation responses to HCV antigens were detected by 3H-TdR incorporation (cpm). RESULTS: Balb/c mice immunized with recombinant plasmid pCD-HCV1 three or four times can generate specific antibody responses to HCV antigens and the antibody levels gradually ascend to the plateaus and did not have the trend of descending in 18 weeks detected. The serum antibodies in mice immunized by recombinant plasmid pCD-HCV1 were 100 percent positive when the serum were diluted 40 times and the positive rate of antibody still were 16.6 percent positive when the serum were diluted 320 times. Balb/c mice immunized with recombinant plasmid pCD-HCV1 (100 micrograms, 50 micrograms 10 micrograms/mouse three times respectively) can elicit antibody responses to HCV antigens and the antibody levels of three groups were 0.70 +/- 0.07, 0.33 +/- 0.04 and 0.11 +/- 0.09 respectively. Spleen cells of Blab/c mice injected with pCD-HCV1 three times were induced to produce proliferation responses to HCVc + e specific antigens. CONCLUSIONS: These results demonstrated that constructs expressioning HCV core and envelope proteins can generate anti-HCVc + e specific antibody responses and lymphoproliferation responses in mice, which suggested it to be possible to elicit immune responses to viral epitopes from HCV via DNA immunization with HCV-DNA recombinant and to warrant further investigation as a potential vaccine against HCV infections.

Animals↗

PubMed1999

[Experimental study of immunization of mice with hepatitis C virus genetic vaccine constructs].

OBJECTIVE: To inquire into the immune responses to expression protein in mice immunized with genetic vaccine of hepatitis C virus (HCV) and lay a foundation for HCV genetic vaccine development in future. METHODS: The gene fragments coding C and most E regions of HCV-II type were inserted into pCD-SRalpha(1) of eukaryotic expression vector and formed genetic vaccine constructs of pCD-HCV(1) and then was injected into the quadriceps muscles of Balb/c mice. The serum anti-HCV level of mice was tested by ELISA and peripheral blood mononuclear cell (PBMC) proliferative responses to HCV antigens were detected by (3)H-TdR incorporation method (cpm). RESULTS: The serum antibody level reached to 0.71 +/- 0.08 - 0.77 +/- 0.06 (A value, the same below) after genetic vaccine pCD-HCV(1) (100 microg/mouse) were inoculated into the mice (n = 12) three or four times while blank vector pCD-SRalpha(1) could not induce the mice (n = 8) to generate antibody response in same way. After the antibody levels in mice (n = 8) immunized by pCD-HCV(1) had ascended to peak value (0.71), there was no trend of descending during the following 18 weeks of detection (0.68 +/- 0.06 - 0.75 +/- 0.07). Specific fragment of HCV cDNA identified by polymerase chain reaction (PCR) from DNA extracted from the muscles of the mice after pCD-HCV(1) had been inoculated three months. PBMC proliferative responses to HCV synthetic peptides CP(9) and gene recombinant antigens C, E(1) in the mice immunized with pCD-HCV(1) were detected and its stimulation indexes (SI) were 4.07 +/- 1.58, 3.88 +/- 0.70 and 3.69 +/- 1.13 respectively and there was a significant difference (P < 0.001) as compared with that of PBMC in mice immunized with pCD-SRalpha(1). CONCLUSION: These investigations demonstrated that genetic vaccine constructs made of HCV structural region can induce Balb/c mice to generate antibody and PBMC proliferative responses to HCV antigens via DNA immunization.

Animals↗

PubMed1998

Frequency and intensity discrimination measured in a maximum-likelihood procedure from young and aged normal-hearing subjects.

A maximum-likelihood method was applied in measurements of frequency and intensity discrimination for aged and young normal-hearing subjects with closely matched audiograms. This method was preferred over other psychophysical procedures because it is efficient and controls experimental variance, features that are highly desirable for testing aged subjects. In order to implement the method, psychometric functions for each task were also measured from young subjects using a constant-stimuli procedure. For the young subjects, the differential thresholds obtained from these two procedures were generally comparable. Further, both sets of data were consistent with previous literature, indicating that the maximum-likelihood method was successfully applied for frequency and intensity discrimination. A frequency-dependent difference between young and aged subjects in both frequency and intensity discrimination was observed. Even with closely matched audiograms, aged subjects demonstrated poorer discrimination abilities than young subjects. The age-related difference was always largest at 500 Hz and decreased as frequency increased.

Adolescent↗

PubMed1998

A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Linkage studies have shown that the majority (approximately 85%) of cases are due to mutations in PKD1 on chromosome 16p, while mutations in PKD2 on chromosome 4q account for most of the remaining cases. Locus heterogeneity in ADPKD is known to contribute to differences in disease severity, with PKD1-linked families having earlier onset of end-stage renal disease (ESRD) than PKD2-linked families (mean age at ESRD: 56 versus 70, respectively). In this study, 11 Canadian families with ADPKD were screened for PKD2 mutations. In four families, linkage to PKD2 was previously documented. In the remaining seven smaller families, one or more affected members had late-onset ESRD at age 70 or older. Using single-stranded conformational polymorphism analysis, one affected member from each family was screened for mutations in all 15 exons of PKD2, which were PCR-amplified from genomic templates. A spectrum of mutations was found in approximately 73% (8 of 11) of the families screened, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In three unrelated families, insertion or deletion of an adenosine in a polyadenosine tract (i.e., (A)8 at nt 2152-2159) was found on exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from "slipped strand mispairing." All mutations, scattered between exons 1 and 11, are predicted to result in a truncated polycystin 2 that lacks both the calcium-binding EF-hand domain and the two cytoplasmic domains required for the interaction of polycystin 2 with polycystin 1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. Thus, these findings are consistent with other recently published reports and suggest that most PKD2 mutations are inactivating.

Adolescent↗

PubMed1998

Experimental model of renovascular hypertension.

OBJECTIVE: To establish a model of renovascular hypertension. METHODS: A 4/0 resorbable chromic catgut ligature was used to ligate subtotally the renal arteries of 18 dogs, forming experimental renovascular hypertension steadily. Blood pressure, plasma renin activity, the ultrastructural changes of juxtaglomerular apparatus and renal artery wall were studied after the constriction. RESULTS: It was reasonable that renal blood flow measured with an electromagnetic flowmeter was reduced by 30% after the constriction. The pathological changes of the induced renal artery stenosis were similar to those of fibromuscular dysphasia. CONCLUSION: The findings provide valuable evidence for the treatment of renovascular hypertension.

Animals↗

PubMed1997

Correlation between direct binding ability of synthetic T. gondii SAG1 peptides to HLA-A2 measured by a sensor for surface plasmon resonance and antigenicity of the peptides for T. gondii-infected cell-specific CTL.

Toxoplasma gondii (T. gondii) -infected B lymphoma cells present T. gondii antigens in the context of major histocompatibility complex molecules to T. gondii-specific CD8+ cytotoxic T cells (CTL). HLA-A2 molecules of T. gondii-infected human cells have been shown to be used in presenting T. gondii antigens to CD8+ CTL. SAG1, one of the major antigenic molecules of T. gondii, is an antigen for T. gondii-specific CTL, and represents a possible basis for vaccines. The direct binding of nonamer SAG1 peptides to HLA-A2 was assayed here using an automated biosensor system with a sensor for surface plasmon resonance detection. The antigenicity of synthetic SAG1 peptides to T. gondii-specific CD8+ CTL also was assayed. The present study found a high correlation between the binding ability of synthetic SAG1 peptides to HLA-A2 and the antigenicity of peptides to T. gondii-infected cell-specific CD8+ CTL.

Animals↗

PubMed1997

Evidence for the effect of gender on activity of (S)-mephenytoin 4'-hydroxylase (CYP2C19) in a Chinese population.

There is evidence that the sex-dependent expression of individual forms of the human cytochrome P450s (CYPs) results in gender-related differences in the hepatic metabolism of certain drugs. Previous work has shown that conflicting evidence exists relating to the sex differences in the activity of (S)-mephenytoin 4'-hydroxylase (CYP2C19). Accordingly, we assessed the effect of gender on CYP2C19 activity in a phenotyped and genotyped healthy unrelated Chinese population for further evidence of such a gender-based differentiation. One hundred and sixteen females and 129 males took one tablet of 100 mg racemic mephenytoin (Mesantoin, Sandoz) after emptying their urinary bladders. Amounts of (S)- and (R)-mephenytoin and its metabolite 4'-hydroxymephenytoin (4'-OH-M) excreted in the postdose 0-8 h urine collection were determined by GC and HPLC methods, respectively. The CYP2C19 activity was expressed as the ratio of S/R-mephenytoin (S/R-ratio), the percentage of the dose excreted as 4'-OH-M (D%), and the log10 of the hydroxylation index which was defined as the ratio of micromoles of (S)-mephenytoin dose to micromoles of 4'-OH-M excreted in urine (1g HI). From all the subjects studied, 53 extensive metabolizers (EMs) and 19 poor metabolizers (PMs) phenotyped were randomly selected and the DNA extracted from their blood samples was utilized for genotyping analysis according to the previously developed standard procedures. In this population, the phenotype PMs were identified in 10.9% (14/128) of the males, as compared with 11.2% (13/116) of the females (chi 2 = 0.0045, df = 1; p > 0.05). In all phenotyped subjects, the S/R-ratio of EM males was significantly higher than that of EM females (mean +/- SD; 0.28 +/- 0.17 vs. 0.24 +/- 0.15; p = 0.030), but no sexual differentiation was observed (p > 0.05) in 4'-OH-M excreted among all EMs and PMs, or the S/R-ratio among all PMs. In all genotyped EMs, the frequency of homozygous EMs was 18.4% higher in females (51.7%, 15/29) than in males (33.3%, 8/24) although there was no significant difference (chi 2 = 1.1370, df = 1, p > 0.05), but the S/R-ratio was lower in homozygous females than in homozygous males (0.22 +/- 0.14 vs. 0.33 +/- 0.09; p = 0.046). Thus, we conclude that the higher CYP2C19 activity in females exists among both the phenotyped EMs and the genotyped homozygous EMs compared with that in males, and that the defect frequency of the enzyme activity is equal between the genders. We also conclude that the S/R-ratio is more a sensitive metabolic marker of CYP2C19 enzyme activity than the D% and 1g HI.

Adolescent↗

PubMed1997

Fine structure of the 2 f1-f2 acoustic distortion products: effects of primary level and frequency ratios.

The fine structure of the 2 f1-f2 acoustic distortion product (ADP) was measured in humans with different primary level (L1/L2) and frequency (f2/f1, f2 > f1) ratios. The (L1/L2) ratio was varied under two conditions. In the first condition L1 was fixed at 50 dB SPL while L2 was varied from 30 to 75dB SPL in 5-dB steps. An upward frequency shift was observed in the ADP fine structure as L2 was increased. In the second condition, L2 was fixed at 50 dB SPL and L1 varied, and a downward frequency shift was observed. These opposing frequency shifts are predicted by a vector-sum model [Sun et al., J. Acoust., Soc. Am. 96, 2166-2174, 2175-2183 (1994)] and support the hypothesis that the ADP fine structure largely reflects place features of the area of overlap of the primary traveling waves. The mechanisms underlying the shifts in fine structure were further investigated by using three primary f2/f1 ratios: 1.11, 1.2, and 1.33. An orderly difference in the rate of fine-structure shift with level was observed as a function of f2/f1 ratio, with the largest rate of shift associated with the smallest frequency ratio. This observation, along with the fact that downward frequency shift (with L1 varied) is always at a larger rate than the upward shift (with L2 varied), suggests that ADP levels and fine structure are strongly influenced by the nonlinear compression present in the mechanics of the basilar membrane in the region of overlap between the primary traveling waves.

Adult↗

PubMed1997

[Construction of recombinant vaccinia virus expressing HSV-2 gD gene as live recombinant vaccine strain].

We had reported that the recombinant vaccinia virus expressing glycoprotein D of herpes simplex virus type 2 (HSV-2 gD) protected mice against lethal HSV-2 challenge. Following the succeed in animal model, we continue the research to construct the recombinant vaccinia virus expressing HSV-2 gD gene as live recombinant vaccine strain in strict accordance with the guideline for human vaccine research. A PCR-modified HSV-2 gD gene was inserted into the plasmid pJSB1175, under the control of P7.5K early/late promoter of vaccinia virus. The recombinant plasmid was used, with lipofectin reagent, to transfect 2BS cells which had been infected by wild type of TK+ vaccinia virus (Tian Tan 761 strain). The recombinant vaccinia virus harboring HSV-2 gD gene was selected out by using in situ hybridization employing 32P-1a-belled HSV-2 gD fragment as probe, together with three cycles of plaque purification. Dot and Southern blot confirmed HSV-2 gD gene had been integrated into the TK region of vaccinia virus genome, as expected. Indirect immunofluorescent assay using anti-HSV-2 gD monoclonal antibody showed HSV-2 gD was expressed effectively in the recombinant virus infected cells.

Animals↗

PubMed1997

Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele.

The incidence of the S-mephenytoin polymorphism was compared in two Chinese ethnic groups, Han (n = 101) and Bai (n = 202) by phenotype and genotype analysis. The frequency of poor metabolizers (PMs) in Han vs. Bai subjects was 19.8% vs. 13.4%. Han subjects had a higher frequency of the mutant CYP2C19m1 allele (0.366 vs. 0.257, P < .01) and a lower frequency of the wild-type allele (0.559 vs. 0.688, P < .01) than Bai subjects, which is consistent with the difference in the frequencies of PMs between the two ethnic groups. This results in a lower percentage of homozygous wild-type extensive metabolizers of mephenytoin (EMs) in Han subjects than in Bai subjects (40% vs. 59%, P = .005). Therefore, Han subjects may be more susceptible than Bai subjects to the drugs metabolized by the CYP2C19 enzyme. Ratios of urinary S/R-mephenytoin in homozygous EMs were lower than those of heterozygous EMs for both Han and Bai subjects, which shows a gene-dosage effect. Genotype analysis identified all but one PM as homozygous or heterozygous for the two known mutant CYP2C19m1 and/or CYP2C19m2 alleles. A single Bai PM outlier was shown to be heterozygous for CYP2C19m1 and a new mutant CYP2C19 allele containing a single amino acid change of Arg433 --> Trp433. A genotyping test demonstrated that only this one individual carried this rare allele (frequency of 0.0025 in Bai subjects).

Alleles↗