PubMed Health⌕ Search

Biomedical subjects

H H Zhou

Publications and source records attributed to H H Zhou.

At least 37 records · Page 2Linked to original sources
PubMed2000

Ethnic differences in drug metabolism.

Ethnic differences in drug metabolism are well documented for a number of drugs. The molecular mechanisms responsible for ethnic differences in drug metabolism have been partly clarified because of the advances in molecular biology in recent years. Gene dosage determines the drug metabolism as demonstrated for S-mephenytoin and diazepam metabolism. Genotype analysis indicates a different frequency for the mutant alleles in different ethnic populations, which results in variations in the frequency of subjects who are homozygous for the mutant allele among the extensive metabolizers in different ethnic populations. Ethnic differences in drug metabolism may result from differences in distribution of a polymorphic trait and mutations which code for enzymes with abnormal activity which occur with altered frequency in different ethnic groups.

Asian People↗
PubMed2000

5-hydroxylation of omeprazole by human liver microsomal fractions from Chinese populations related to CYP2C19 gene dose and individual ethnicity.

It has been previously reported that omeprazole (OP) oxidation is mediated by CYP2C19 and CYP3A4 in human livers. In this study, we assessed their relative contributions with human liver microsomal fractions from Chinese populations that were genotyped by CYP2C19 and recruited from two ethnic groups, Han and Zhuang. The kinetics of 5-hydroxyomeprazole (5-OH-OP) formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equations for liver microsomes from CYP2C19 extensive (EMs) and poor metabolizers, respectively. At a low substrate concentration that may be encountered in vivo, the monoclonal antibody to CYP2C8/9/19 strongly inhibited 5-OH-OP formation in EM microsomes, whereas troleandomycin (TAO) eliminated most of the formation at a high substrate concentration. In poor metabolizer microsomes, either TAO or anti-CYP3A4 could alone abolish 5-OH-OP formation. Furthermore, there were differences between homozygous and heterozygous EMs in the percentage of inhibition by TAO and the antibodies. At the low substrate concentration, OP 5-hydroxyaltion was correlated well with S-mephenytoin 4'-hydroxylation and CYP2C19 contents in liver microsomes of 34 Chinese individuals. Moreover, in these individuals, obviously genetic and somewhat ethnic differences in OP 5-hydroxylation were observed between different CYP2C19 genotypes (wt/wt > wt/m1 > m1/m1) and between Han and Zhuang (Han > Zhuang), respectively. The results indicate that CYP2C19 is a high-affinity enzyme for OP 5-hydroxylation by liver microsomes from Chinese individuals and that its contribution is CYP2C19 gene dependent and ethnically related. Similar studies indicate that OP sulfoxidation is mediated mainly by CYP3A4 and independent of CYP2C19 genotype status.

Adult↗
PubMed2000

Contribution of genetic variations in estradiol biosynthesis and metabolism enzymes to osteoporosis.

The occurrence of osteoporosis is closely related to serum estradiol level. CYP19 is the most important biosynthesis enzyme and CYP1A2, CYP3A4, and 17 beta-HSD are important metabolism enzymes. Any changes in these enzymes activity affects estradiol biosynthesis or metabolism, and changes the estradiol serum level. By reviewing the recent literature, it was found that the genetic variations of CYP19, CYP1A2, CYP3A4, and 17 beta-HSD are important factors affecting the estradiol serum level, and may be closely related to the development of osteoporosis.

Animals↗
PubMed2000

Determination of procaterol in human plasma by gas chromatography/electron impact ionization mass spectrometry.

AIM: To improve a gas chromatography/electron impact ionization mass spectrometry (GC/MS) method for determining the concentration of procaterol in human plasma. METHODS: GC/MS was developed with capillary column. Samples were extracted by liquid phase before derivated. Imipramine was used as an internal standard. The injector and GC/MS interface temperatures were set at 280 degrees C and 250 degrees C, respectively. The carrier gas (helium) was 0.8 mL.min-1, and injections were made in the pulse-splitless mode. The MS source and MS Quad temperature were 230 degrees C and 150 degrees C, respectively. RESULTS: The detection limit of plasma procaterol was 5 ng.L-1. The assay was linear over the range of 10-10,000 ng.L-1 with correlation coefficient of 0.9987. The coefficients of variation were less than 10% for procaterol detection at high, medium and low concentration levels (n = 5). The average recovery of the assay was 99.1% +/- 1.3%. CONCLUSION: This assay was sensitive, precise, and accurate for evaluating the clinical pharmacokinetics of procaterol.

Bronchodilator Agents↗
PubMed2000

Determination of fluoxetine and its metabolite norfluoxetine in human liver microsomes by reversed-phase HPLC in vitro.

AIM: A high-performance liquid chromatography (HPLC) method was developed for the determination of fluoxetine (FLU) and its metabolite norfluoxetine (N-FLU) in human liver microsomes in vitro. METHODS: An incubation buffer containing human liver microsomes, NADPH-generating system, and FLU, after termination of enzyme reaction and addition of nortriptyline (NOR) as internal standard (IS), was extracted with n-hexane/acetonitrile, and separated on a reversed-phase ODS column. Detection was achieved at 226 nm by ultraviolet detector (UV). RESULTS: The limit of detection was 5 micrograms/L for both FLU and N-FLU. No potential interference was found. The method provides recoveries of up to 94%-104% and acceptable coefficients of variation were found for both within-run (< 7.8%) and day to day (< 9.1%) assays. CONCLUSION: This method is rapid, sensitive, and simple for studying the metabolism of FLU and N-FLU.

Chromatography, High Pressure Liquid↗
PubMed2000

G-2964A and C734A genetic polymorphisms of CYP1A2 in Chinese population.

AIM: To observe the G-2964A and C734A genetic polymorphisms of human CYP1A2 in Chinese population. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed in genotyping analysis. RESULTS: The allele frequencies of A-2964 were 0.25 and 0.22 in Qidong and Changsha populations, respectively. The incidences of A734 were 0.68 in Qidong population and 0.66 in Changsha population. No more than two low-inducibility/activity alleles were presented in one person. CONCLUSION: The distribution of the G-2964A and C734A genetic polymorphisms did not show significant difference between Chinese and Japanese populations. The incidence of C734A in Chinese was also similar to that in Caucasian population.

Adult↗
PubMed2000

Polymorphism of CYP450 and cancer susceptibility.

CYP450s form a superfamily involved in the metabolism of many endogenous and exogenous substrates. In this review, the substrates, probe drugs, genetic polymorphisms, and associated cancers of CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are summarized.

Breast Neoplasms↗
PubMed2000

In vitro proguanil activation to cycloguanil is mediated by CYP2C19 and CYP3A4 in adult Chinese liver microsomes.

AIM: To identify the cytochrome P450 isoforms involved in proguanil (PG) activation to cycloguanil (CG) in Chinese liver microsomes. METHODS: The kinetics of the CG formation from PG was determined in the liver microsomes of 6 Chinese subjects. Selective chemical inhibitors to various cytochrome P450 isoforms were employed to conduct inhibition experiments. The relationship between the CG formation and S-mephenytoin 4'-hydroxylation was analyzed. RESULTS: The kinetic behaviors of CG formation were described well by a single-enzyme Michaelis-Menten equation in five livers. The apparent Km and Vmax were (82 +/- 47) mumol.L-1 and (8 +/- 6) pmol.min-1.mg-1 protein, respectively. However, the remaining one displayed a two-enzyme kinetic behavior. Inhibition experiments showed that troleandomycin (100 mumol.L-1) and diethyldithiocarbamate (100 mumol.L-1), as potent CYP3A4 and CYP2E1 inhibitors, respectively, reduced the formation rate of CG by 81.1% and 47.23%, while quinidine (10 mumol.L-1), furafylline (20 mumol.L-1), and sulfaphenazole (10 mumol.L-1), which were inhibitors towards CYP2D6, 1A2 and 2C9/10, respectively, did not display significant inhibition. At a low PG concentration of 5 mumol.L-1, the CG formation correlated well with S-mephenytoin 4'-hydroxylation (r = 0.805, P < 0.05). Nevertheless, when a high substrate concentration (500 mumol.L-1) was used, the correlation coefficient decreased (r = 0.581, P < 0.05). CONCLUSION: The present study indicates that CYP3A4 and CYP2C19 are involved in PG activation to CG in adult Chinese liver microsomes. CYP2C19 played an important role in the clearance of PG at a substrate concentration close to in vivo therapeutic concentrations, while CYP3A4 gradually made a dominant contribution with the increase of PG concentration.

Adult↗
PubMed2000

Probing CYP2C19 and CYP3A4 activities in Chinese liver microsomes by quantification of 5-hydroxyomeprazole and omeprazole sulphone.

AIM: To develop an analytical method for simultaneous quantification of 5-hydroxyomeprazole (5-OH-OP) and omeprazole sulfone (OPS), and explore whether omeprazole (OP) is an appropriate phenotypic probe for CYP2C19 and CYP3A4 in Chinese liver microsomes. METHODS: OP metabolism in vitro was conducted in Chinese liver microsomes, and the major metabolites 5-OH-OP and OPS were determined using high pressure liquid chromatography (HPLC). Monoclonal antibodies anti-CYP2C8/9/19 and anti-CYP3A4 were employed to conduct inhibition experiments. The protein contents of CYP2C19 and CYP3A4 were quantified using Western blot analysis and densitometric scanning. RESULTS: 5-OH-OP and OPS gave a baseline resolution in the HPLC analysis. The detection limits for both compounds were 0.01 nmol and the recovery (98%-102%) had good precision with relative standard deviation of < 9.5%. Both anti-CYP2C8/9/19 and anti-CYP3A4 had a significant inhibitory effect (P < 0.05) on the 5-OH-OP formation in a substrate concentration-dependent manner, and anti-CYP3A4 alone could almost abolish the formation of OPS (> 87%). At a substrate concentration of 2 mumol/L OP, good correlations were found between OP 5-hydroxylation and S-mephenytoin 4'-hydroxylation activities (r = 0.72, P < 0.01), OP 5-hydroxylation activities and CYP2C19 contents (r = 0.82, P < 0.01), and OP sulfoxidation activities and CYP3A4 contents (r = 0.78, P < 0.01) in Chinese liver microsomes. CONCLUSION: OP metabolism is mediated mainly by CYP2C19 and CYP3A4, and OP can be used to probe CYP2C19 and CYP3A4 activities in Chinese liver microsomes at appropriate substrate concentrations with the HPLC method presently developed.

2-Pyridinylmethylsulfinylbenzimidazoles↗
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

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

Specificity of inducible nitric-oxide synthase inhibitors: prospects for their clinical therapy.

Nitric oxide (NO) is a ubiquitous, naturally occurring molecule found in a variety of cell types and organ systems. It is a double-edged sword, beneficial as a messenger or modulator and for immunology self-defense, but potentially toxic. The formation and signal function of nitric oxide are mainly modulated by nitric-oxide synthase (NOS). Up to the present, a number of diseases, including circulatory shock, atherosclerosis, cardiac allograft rejection, chronic inflammation, cardiac infarction, cancer and so on, have been demonstrated that their pathogenesis may be involved in the sustained production of large quantities of nitric oxide. Animal studies and human studies have shown that specific inhibitors of inducible nitric-oxide synthase may be useful in the therapy of a variety of diseases associated with induction of nitric-oxide synthase. In this review, we compare and contrast these inhibitors along with examples of their use in the studies of medicine.

Animals↗
PubMed1998

The induction effect of rifampicin on activity of mephenytoin 4'-hydroxylase related to M1 mutation of CYP2C19 and gene dose.

AIMS: To determine the induction effect of rifampicin on the activity of 4'-hydroxylase in poor metabolizers (PMs) with m1 mutation of S-mephenytoin 4'-hydroxylation and the relationship of the effect with gene dose. METHODS: Seven extensive metabolizers (EMs) of S-mephenytoin 4'-hydroxylation and five PMs with m1 mutation were chosen to take rifampicin 300 mg day(-1) orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100 mg. The 4'-hydroxymephenytoin (4'-OH-MP) excreted in the 0-24 h urine and mephenytoin S/R ratio in the 0-8 h urine were determined by h.p.l.c. and GC, respectively. RESULTS: In all EMs, the excretion of 4'-OH-MP in the 0-24 h urine was increased by 146.4 +/- 17.9%, 0-8 h urinary mephenytoin S/R ratio was decreased by 77.3 +/- 8.8%, the percentage increase in the 0-24 h excretion of 4'-OH-MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m1 and wt/m2) (203.9 +/- 42.5% vs 69.6 +/- 4.1%). 0-8 h urinary mephenytoin S/R ratio of those PMs with m1 mutation was decreased by 9.6%, the amount of 4'-OH-MP excreted in the 0-24 h urine was increased by 80.1 +/- 48.0%. CONCLUSIONS: The activity of 4'-hydroxylase of PMs with m1 mutation of S-mephenytoin 4'-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4'-hydroxylase is gene dependent.

Adult↗
PubMed1998

Hyper- and hypoventilation affects spinal motor neuron excitability during isoflurane anesthesia.

UNLABELLED: Increasing evidence indicates that the spinal cord is an important site of anesthetic action necessary for surgical immobility. Whether clinical hyper- or hypoventilation affects motor neuron excitability during general anesthesia is unknown. To clarify this issue, we studied seven adult ASA physical status I or II patients undergoing elective surgery. Spinal motor neuron excitability was determined by measuring the posterior tibial nerve H reflex and F wave. The baseline H reflex and F wave were recorded before anesthesia using electrodes placed over the soleus and abductor hallucis muscles. After inhaled induction, the end-tidal isoflurane concentration in O2 was maintained at 0.8%. Ventilation was controlled to maintain a steady-state ETCO2 of 25 +/- 1 and 45 +/- 1 mm Hg randomly for 20 min. Then the H-reflex and F wave were recorded. The difference in H reflex and F wave were analyzed using Student's paired t-test. The baseline H-reflex amplitude (6.8 +/- 2.7 mV) decreased to 4.0 +/- 2.0 mV (P < 0.01) at an ETCO2 of 25 mm Hg and to 2.0 +/- 2.2 mV (P < 0.01) at an ETCO2 of 45 mm Hg. The F-wave persistence (100%) decreased to 77% +/- 24% (P < 0.05) at an ETCO2 of 25 mm Hg and to 61% +/- 19% at an ETCO2 of 45 mm Hg (P < 0.01). Changing ETCO2 values affected H-reflex amplitude and F-wave persistence (P < 0.05), which suggests a change of spinal cord motor neuron excitability, which may affect surgical immobility. IMPLICATIONS: The spinal cord is important for preventing patient movement during surgery. The likelihood of movement may be predicted by measuring the spinal motor neuron excitability by using the H reflex and F wave. Our results show that intraoperative hyper- and hypoventilation can change the H reflex and F wave, which may affect the probability of patient movement during surgery.

Action Potentials↗
PubMed1998

Suppression of spinal cord motoneuron excitability correlates with surgical immobility during isoflurane anesthesia.

BACKGROUND: Recent evidence suggests that the spinal cord is an important site of anesthetic action that produces surgical immobility. Inhalation anesthetics depress the Hoffmann's reflex (H reflex) and F wave, indicating spinal motoneuron suppression. The aim of this study was to assess the correlation between isoflurane-induced immobility and H- and F-wave suppression. METHODS: The baseline H reflex and F wave were measured before anesthesia in 15 adult patients. After induction, 1% end-tidal isoflurane was maintained for 20 min before the H and F waves were reelicited. Using an electric stimulus applied to the forearm and grading the response as movement or no movement, the authors increased or decreased the isoflurane concentration in 0.1% steps, depending on the movement responses. The H and F waves were recorded 20 min after each change of isoflurane concentration. The correlation between H- and F-wave suppression and surgical immobility was analyzed using a paired t test with Bonferroni correction. RESULTS: H-reflex amplitude (2.74 +/- 1.63 mV) and F-wave persistence (70.69 +/- 26.19%) at the highest isoflurane concentration that allowed movement response to a stimulus are different (P < 0.01) from these (1.97 +/- 1.46 mV; 43.16 +/- 22.91%) at the lowest isoflurane concentration that suppressed response. At 0.8% isoflurane, the H-reflex amplitude was 3.69 +/- 1.83 mV with movement and 1.01 +/- 1.14 mV without movement (P < 0.01); F-wave amplitude was 0.29 +/- 0.15 mV with movement and 0.11 +/- 0.06 mV without movement (P < 0.01); F-wave persistence was 80 +/- 22.36% with movement and 34.9 +/- 25.75% without movement (P < 0.01). CONCLUSIONS: The degree of H- and F-wave amplitude and F-wave persistence suppression correlates with movement response, suggesting that isoflurane-suppressive action in the spinal cord plays a significant role in producing surgical immobility.

Adult↗
PubMed1998

Use of caffeine as a probe for rapid determination of cytochrome P-450 CYP1A2 activity in humans.

AIM: To develop a rapid HPLC method for the determination of cytochrome P-450 CYP1A2 activity. METHODS: A 300-microL plasma was prepared by extraction with 5-mL chloroform/isopropanol (9:1), and beta-hydroxyletheophylline was added as internal standard (IS). Samples were separated on an ODS column by a gradient elution system, of which mobile phase consisted of 0.05% acetic acid, acetonitrile, and methanol. The compounds of interest were monitored at 282 nm by UV detector. RESULTS: No potential interfering peaks were found. Paraxanthine (17X), IS and caffeine (137X) were rapidly eluted with baseline resolution, and their retention time was less than 13 min. The detection limits of both 17X and 137X were 0.1 mumol.L-1. Linear relations ranged over 1-100 mumol.L-1 and 1-200 mumol.L-1 with correlation coefficient of 0.9999 and 0.9987, respectively, for 17X and 137X. The coefficients of variation were within 6% for 17X, and 10% for 137X. The average recoveries for both compounds were ranged from 96% to 108%. CONCLUSION: This method is sensitive and rapid, and can be used for population studies of CYP1A2.

Caffeine↗