Biomedical subjects

H Yamazaki

Publications and source records attributed to H Yamazaki.

At least 235 records · Page 13Linked to original sources

PubMed1998

A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin- 3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors.

A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.

Animals↗

PubMed1998

Immunoglobulin-A and -G responses against virus-like particles (VLP) of human papillomavirus type 16 in women with cervical cancer and cervical intra-epithelial lesions.

Immunoglobulin-A and -G (IgA and IgG) responses against HPV-16-like particles (VLP) were tested by ELISA in 104 women with cervical abnormalities, 26 atypical cells of undetermined significance (ASCUS) and 14 cytologically normal women with HPV DNA. As controls, 130 age-matched cytologically normal women with no HPV DNA were selected from the population in which the cases were generated. The existence of HPV DNA in cervical samples was tested by a PCR-based method. The normal women positive with HPV-16 DNA were followed up at 4- to 7-month intervals for 16 to 24 months. IgA and IgG antibodies against HPV-16 VLP were frequently detected in these women repeatedly positive with HPV-16 DNA, suggesting that persistent HPV infection is crucial for effective antibody responses against the viruses. IgA response appears earlier and persists longer than IgG response. Women with HPV DNA of types 16, 31/33/35, 58 and unknown types showed significantly higher seropositivity for both IgA and IgG antibodies than the controls (p < 0.05 for both). No significant seropositivity for IgA or IgG was detected in the HPV-18/45-DNA-positive group. HPV 31/33/35, 58 appear to be types close to HPV 16, whereas HPV 18/45 appears to be distinct from HPV 16 in antigenicity. IgA and IgG responses against HPV-16 VLP were more frequently observed in women with normal cervices with HPV DNA, ASCUS, HSIL and cervical cancer than in the controls. Strong IgA and IgG responses depended on HPV-16 infection in HSIL and cervical cancer, but there was no correlation between the serological responses and the status of HPV DNA in ASCUS and LSIL. Antibody positivity reflects persistent viral infection that may increase the risk for malignant progression of the cervix. This serological assay using HPV-16 VLP may therefore be useful as a new diagnostic tool supplementing cervical cytological tests.

Adult↗

PubMed1998

Establishment and characterization of an immortal macrophage-like cell line inducible to differentiate to osteoclasts.

Osteoclasts are hematopoietic cells essential for bone remodeling and resorption. To understand the process of osteoclast development, we established a macrophage-like cell line C7 that has the potential to differentiate into functional osteoclasts; multinuclear tartrate-resistant acid phosphatase positive cells capable of forming pits on dentin slices. C7 cells share the characteristics of their cell surface molecules and phagocytic activity with macrophages. Generation of osteoclasts from C7 cells was mostly suppressed by the addition of a function-blocking antibody directed to c-Fms, the receptor for macrophage-colony stimulating factor (M-CSF), or by osteoclastogenesis inhibitory factor (OCIF). These responses correspond well with the osteoclast precursors present in bone marrow and peritoneal cavity. Reagents such as bacterial lipopolysaccharide and granulocyte/macrophage-CSF that are known to act as inducers for other cell lineages rather than osteoclasts abolished the potential of osteoclastogenesis in C7 cells. These phenotypes of C7 cells have been stably maintained for more than 2 years. We believe that the cell line established in this study will provide an important tool for osteoclast biology.

Antibodies↗

PubMed1998

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats.

(+/-)-Pantoprazole ((+/-)-PAN), (+/-)-5-(difluoromethoxy)-2-[[3.4-dimethoxy-2-pyridinyl)methyl]sul finyl]- 1H-benzimidazole) is a chiral sulfoxide that is used clinically as a racemic mixture. The disposition kinetics of (+)-PAN and (-)-PAN given separately has been studied in rats. Serum levels of (+)- and (-)-PAN and its metabolites, pantoprazole sulfone (PAN-SO2), pantoprazole sulfide (PAN-S), 4'-O-demethyl pantoprazole sulfone (DMPAN-SO2), and 4'-O-demethyl pantoprazole sulfide (DMPAN-S) were measured by HPLC. Following single intravenous or oral administration, both enantiomers were rapidly absorbed and metabolized, resulting in similar serum concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics. The major metabolite of both (+)- and (-)-PAN was PAN-SO2, while DMPAN-SO2 was also detected as a minor metabolite. Serum levels of PAN-S and DMPAN-S could not be quantified after intravenous or oral administration of either enantiomer. Significant chiral inversion occurred after intravenous and oral administration of (+)-PAN. The AUCs of (-)-PAN after intravenous and oral dosing of (+)-PAN were 36.3 and 28.1%, respectively of those of total [(+) + (-)] PAN. In contrast, the serum levels of (+)-PAN were below quantitation limits after intravenous or oral administration of (-)-PAN. Therefore, chiral inversion was observed only after administration of (+)-PAN, supporting the hypothesis that stereoselective inversion from (+)-PAN to (-)-PAN occurs in rats.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1998

Production of trehalose synthase from a basidiomycete, Grifola frondosa, in Escherichia coli.

The genomic DNA and cDNA for a gene encoding a novel trehalose synthase (TSase) catalyzing trehalose synthesis from alpha-D-glucose 1-phosphate and D-glucose were cloned from a basidiomycete, Grifola frondosa. Nucleotide sequencing showed that the 732-amino-acid TSase-encoding region was separated by eight introns. Consistent with the novelty of TSase, there were no homologous proteins registered in the data-bases. Recombinant TSase with a histidine tag at the NH2-terminal end, produced in Escherichia coli, showed enzyme activity similar to that purified from the original G. frondosa strain. Incubation of alpha-D-glucose 1-phosphate and D-glucose in the presence of recombinant TSase generated trehalose, in agreement with the enzymatic property of TSase that the equilibrium lay far in the direction of trehalose synthesis.

Amino Acid Sequence↗

PubMed1998

Phase II trial of combination chemotherapy with cisplatin, carboplatin and etoposide in stage IIIB and IV small-cell lung cancer. Fukuoka Lung Cancer Study Group.

PURPOSE: A phase II trial combining cisplatin, carboplatin and etoposide was conducted in previously untreated patients with stage IIIB and IV small-cell lung cancer, in an attempt to increase response rates and prolong survival. METHODS: Previously untreated patients with small-cell lung cancer, with measurable disease, aged < or = 72 years, performance status < or = 2, and adequate hematologic, hepatic and renal function were enrolled in the study. They were treated with 80 mg/m2 cisplatin on day 1, 100 mg/m2 carboplatin on days 2, 3 and 8, and 50 mg/m2 etoposide on days 1, 2, 3 and 8. RESULTS: A total of 46 patients (20 with stage IIIB and 26 with stage IV disease) were enrolled in the study. A total of 186 courses of chemotherapy were given, and the dose was reduced in 27 courses (15%). The chemotherapy was repeated for four or more courses in 30 patients. There were 10 complete responses and 32 partial responses, for a total response rate of 91% (95% confidence interval, 79% to 98%). The median survival time and 2-year survival rates were 18 months and 22% for stage IIIB disease, and 14 months and 15% for stage IV disease. Major side effects were hematologic: leukopenia, anemia, and thrombocytopenia of grade 3 or more occurred in 48%, 46%, and 43% of patients, respectively. CONCLUSIONS: The three-drug regimen of cisplatin, carboplatin and etoposide is feasible and active against small-cell lung cancer.

Aged↗

PubMed1998

Alterations in tumour suppressor gene p53 correlate with inhibition of thrombospondin-1 gene expression in colon cancer cells.

If activation of the p53 gene is involved in the progression or metastasis of colon cancer, it may affect the angiogenic phenotype in vivo. To verify this hypothesis, we studied the correlation between p53 accumulation and expression of thrombospondin-1 (TSP1) in colon cancer specimens. Levels of TSP1 gene expression were estimated by Northern blotting in 65 colon cancers. Accumulation of p53 and the distribution of TSP1 protein were evaluated immunohistochemically. Various levels of TSP1 gene expression were seen in colon cancers, while p53 accumulation was confirmed in 42 of the 65 colon cancers. The level of TSP1 gene expression demonstrated a significant inverse correlation with p53 accumulation in colon cancer. Colon cancer cells expressed TSP1 protein and p53 accumulation reciprocally in the same nests. These results suggest that alterations in the tumour suppressor gene p53 may inhibit TSP1 expression in colon cancer.

Adenocarcinoma↗

PubMed1998

Release of a substance that suppresses spontaneous motor activity in the brain by physical exercise.

Injection of the cerebrospinal fluid (CSF) collected from rats fatigued by obligatory swimming into the cisterna magna of mice suppressed the spontaneous motor activity of the mice. The suppressive activity was abolished by heat denaturation of the CSF and was found in the CSF fraction with a molecular weight above 10,000 after ultrafiltration. These findings suggest the presence of a substance(s) released in a fatigued animal's brain that suppresses its spontaneous motor activity and generates the sensation of fatigue.

Animals↗

PubMed1998

Establishment and characterization of pro-B cell lines from motheaten mutant mouse defective in SHP-1 protein tyrosine phosphatase.

Mice homozygous for the motheaten (Hcph(me)) mutation lack a functional SHP-1 protein tyrosine phosphatase, show severe immunologic dysregulation and die at an early age. Severe pneumonitis in me/me mice is associated with abnormal proliferation of macrophages and granulocytes. Overgrowth of macrophages in long term cultures of me/me bone marrow has prevented analyses of lymphopoiesis in vitro. To establish hematopoietic cell lines from me/me mice, we cultured me/me bone marrow with the PA6 stromal cell line in the presence of antagonistic antibody against the receptor (c-Fms) for macrophage colony stimulating factor (M-CSF). In these cultures, overgrowth of M-CSF-dependent macrophages was suppressed by the antagonistic antibody and other hemopoietic cell lineages were generated efficiently from me/me bone marrow. By using this culture system, we established me/me pro-B cell clones (MEBs) with rearranged DH-JH but not VH-DJH. The growth of MEB clones required IL-7 and c-Kit ligand, corresponding to normal pro-B cells which express SHP-1. MEB cells were sensitive to starvation by either IL-7 or c-Kit ligand, resulting in apoptotic death. The present culture system, which supports hematopoiesis of me/me bone marrow, provides useful tools for the determination of the role of SHP-1 in signal transduction of B lymphopoiesis.

Animals↗

PubMed1998

NMDA receptor-mediated inspiratory off-switching in pneumotaxic-disconnected cats.

The pneumotaxic center is thought to govern inspiratory off-switching (IOS), and blockade of N-methyl-D-aspartate (NMDA) receptors by dizocilpine impairs IOS causing apneusis. The present study is to examine whether the NMDA receptor-mediated IOS mechanism functions in the medullary respiratory network after disconnecting the pneumotaxic center. In decerebrate and vagotomized cats, the nucleus parabrachialis medialis (NPBM) and vagus nerves were stimulated to evoke IOS and a dorsal pontine transection was performed while the central respiratory activity was recorded in phrenic neurogram. The transection eliminated the NPBM-stimulated IOS but not the vagally evoked IOS, and developed two types of respiration; eupnea in 12 and apneusis in six out of 18 cats. Apneustic respiration was not changed into eupneic one by changing the end-tidal CO2 level. In animals displaying eupnea after the transection, dizocilpine (0.3 mg/kg i.v.) produced apneusis, characterized by a prolonged inspiration, a shortened stage 1 expiration and an unchanged stage 2 expiration. Dizocilpine caused no further change in the apneustic pattern induced by the transection. The present results suggest that the medullary respiratory network is able to generate a eupneic respiration after disconnecting the pontine pneumotaxic center, and the NMDA mechanism plays an important role in the medullary respiratory network.

Age Factors↗

PubMed1998

Growth stimulation of non-small cell lung cancer xenografts by granulocyte-macrophage colony-stimulating factor (GM-CSF).

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been suggested to be involved in the carcinogenesis of some types of tumours by autocrine or paracrine mechanisms. We examined GM-CSF/GM-CSF receptor (GM-CSFR) gene expression in 20 human non-small cell lung cancer (NSCLC) xenografts. The stimulatory effects of GM-CSF were examined using GM-CSF transgenic severe combined immunodeficient (SCID) mice (GM-Tg-SCID), which produce abundant human GM-CSF. A NSCLC xenograft (LC11-JCK), expressed GM-CSFR but not GM-CSF, and showed more rapid growth in GM-Tg-SCID than non-GM-CSF transgenic SCID mice (non-Tg-SCID). GM-CSF gene expression was detected in 48 of 90 (53%) primary NSCLC human specimens and GM-CSFR gene expression was detected in 42 specimens (47%). GM-CSF expression was detected in 13 of 30 squamous cell carcinoma specimens (43%) and GM-CSFR expression was detected in 10 specimens (33%). Patients with squamous cell carcinoma coexpressing GM-CSF and GM-CSFR showed significantly poorer prognosis than those expressing neither GM-CSF nor GM-CSFR (P < 0.05, Cox-Mantel test). These results suggest that GM-CSF can have a stimulatory effect on some NSCLC.

Animals↗

PubMed1998

Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes.

Of seven cDNA-expressed human cytochrome P450 (P450) enzymes (P450s 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) examined, P450 1A2 was the most active in catalyzing 2- and 4-hydroxylations of estradiol and estrone. P450 3A4 and P450 2C9 also catalyzed these reactions although to lesser extents than P450 1A2. P450 1A2 also efficiently oxidized estradiol at the 16alpha-position but was less active in estrone 16alpha-hydroxylation; the latter reaction and also estradiol 16alpha-hydroxylation were catalyzed by P450 3A4 at significant levels. Anti-P450 1A2 antibodies inhibited 2- and 4-hydroxylations of these two estrogens catalyzed by liver microsomes of some of the human samples examined. Estradiol 16alpha-hydroxylation was inhibited by both anti-P450 1A2 and anti-P450 3A4, while estrone 16alpha-hydroxylation was significantly suppressed by anti-P450 3A4 in human liver microsomes. Fluvoxamine efficiently inhibited the estrogen hydroxylations in human liver samples that contained high levels of P450 1A2, while ketoconazole affected these activities in human samples in which P450 3A4 levels were high. alpha-Naphthoflavone either stimulated or had no effect on estradiol hydroxylation catalyzed by liver microsomes; the intensity of this effect depended on the human samples and their P450s. Interestingly, in the presence of anti-P450 3A4 antibodies, alpha-naphthoflavone was found to be able to inhibit estradiol and estrone 2-hydroxylations catalyzed by human liver microsomes. The results suggest that both P450s 1A2 and 3A4 have major roles in oxidations of estradiol and estrone in human liver and that the contents of these two P450 forms in liver microsomes determine which P450 enzymes are most important in hepatic estrogen hydroxylation by individual humans. P450 3A4 may be expected to play a more important role for some of the estrogen hydroxylation reactions than P450 1A2. Knowledge of roles of individual P450s in these estrogen hydroxylations has relevance to current controversies in hormonal carcinogenesis [Service, R. F. (1998) Science 279, 1631-1633].

Aryl Hydrocarbon Hydroxylases↗

PubMed1998

Selectivity of polycyclic inhibitors for human cytochrome P450s 1A1, 1A2, and 1B1.

Human cytochrome P450s 1A1, 1A2, and 1B1 are known to have overlapping substrate specificities. All are regulated in part by the Ah locus; P450 1A2 is expressed essentially only in liver, but P450s 1A1 and 1B1 are both expressed in many extrahepatic tissues. Twenty-five polycyclic hydrocarbons, many containing acetylenic side chains, were examined as inhibitors of the three enzymes using 7-ethoxyresorufin O-deethylation as the enzyme assay in all cases. Several compounds were inhibitory at low nanomolar concentrations. 1-(1-Propynyl)pyrene and 2-(1-propynyl)phenanthrene nearly completely inhibited P450 1A1 at concentrations at which no P450 1B1 inhibition was observed. 2-Ethynylpyrene and alpha-naphthoflavone (7, 8-benzoflavone) nearly completely inhibited P450 1B1 at concentrations at which no P450 1A1 inhibition was noted. All four of the above compounds also inhibited P450 1A2. Several polycyclic hydrocarbons devoid of acetylenic groups were also inhibitory with respect to all three P450s. Some of the acetylenic compounds examined showed enhanced inhibition following preincubation with the P450s in the presence of cofactors NADPH and O2. However, of seven compounds (five acetylenes) tested with P450 1B1, only two [2-ethynylpyrene and 4-(1-propynyl)biphenyl] showed such evidence for mechanism-based inactivation. We conclude that (i) several polycyclic hydrocarbons and their oxidation products are very inhibitory with respect to human P450s 1A1, 1A2, and 1B1; (ii) of these inhibitors only some are mechanism-based inactivators; and (iii) some of the inhibitors are potentially useful for distinguishing between human P450s 1A1 and 1B1.

Biotransformation↗

PubMed1998

Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer.

Vascular endothelial growth factor (VEGF) is a well known factor that induces angiogenesis. Four isoforms, i.e. VEGF206, 189, 165, and 121, have been identified. We examined the isoform patterns of VEGF mRNA using reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers. All the colon cancers examined expressed VEGF121. The isoform patterns were classified into three groups: type 1, VEGF121; type 2, VEGF121 + VEGF165; type 3, VEGF121 + VEGF165 + VEGF189. Three of the 61 colon cancers examined showed type 1 expression, 26 showed type 2 expression and 32 showed the type 3 pattern. The patients with liver metastases showed the type 3 isoform expression pattern at a significantly higher incidence (12 of 16, 75%) than those without liver metastasis (20 of 45, 44%) (P=0.036). The type 3 isoform pattern was significantly associated with M1 stage (P=0.019). The patients with colon cancer and the type 3 isoform pattern showed significantly poor prognosis (P < 0.01, Cox-Mantel). The colon cancers with the type 3 pattern showed a significantly higher involvement of veins (P=0.006). These observations suggest that the aberrant type 3 expression pattern of VEGF189 mRNA isoforms is correlated with liver metastasis, M stage, and poor prognosis in colon cancer.

Adenocarcinoma↗

PubMed1998

Effect of insulin therapy on body fat distribution in NIDDM patients with secondary sulfonylurea failure: a preliminary report.

OBJECTIVE: To clarify the influence of insulin therapy on body weight and fat distribution, we compared these parameters in five non-insulin dependent diabetes mellitus (NIDDM) patients, with secondary sulfonylurea failure, before and after insulin therapy. Body weight increased significantly after instituting insulin treatment. However, the visceral to subcutaneous fat (V/S) ratio decreased significantly due to a marked increase in S-fat without a change in V-fat. Insulin therapy necessitated by sulfonylurea failure does not appear to accelerate the atherogenic process in NIDDM patients as there is no increase in visceral fat.

Adipose Tissue↗

PubMed1998

Formation in vitro of an inhibitory cytochrome P450 x Fe2+-metabolite complex with roxithromycin and its decladinosyl, O-dealkyl and N-demethyl metabolites in rat liver microsomes.

1. Roxithromycin and its major metabolites found in rat and human urine, namely the decladinosyl derivative (M1), O-dealkyl derivative (M2) and N-demethyl derivative (M3), were incubated with rat liver microsomes and formation of an inhibitory cytochrome P450 (CYP)-metabolite complex and of formaldehyde (measurement of N-demethylation) were determined in vitro. Troleandomycin and erythromycin were also used for comparison. 2. Dexamethasone very significantly induced the microsomal N-demethylations of these macrolide antibiotics. The order of magnitude for the Vmax/Km ratio of N-demethylations by liver microsomes from dexamethasone-treated rats was troleandomycin > erythromycin = M2 > roxithromycin > M3, M1. 3. Formation of an inhibitory P450 x Fe2+-metabolite complex was detected on incubation of these macrolide antibiotics with rat liver microsomes in the presence of an NADPH-generating system and the order of maximum complex formation was troleandomycin > erythromycin > M2 > roxithromycin > M3 > M1. 4. Troleandomycin, erythromycin and M2 inhibited CYP3A-dependent testosterone 6beta-hydroxylation catalysed by liver microsomes from the dexamethasone-treated rat by 54, 33 and 23%, respectively, but roxithromycin, M3 and M1 were very weak by comparison. In the untreated rat, only testosterone 6beta-hydroxylation, but not testosterone 16alpha- and 2alpha-hydroxylation and androstenedione formation, activities were inhibited, indicating that inhibitory actions of these antibiotics are specific for CYP3A enzymes in liver microsomes. 5. These results support the view that formation of an inhibitory P450-metabolite complex is prerequisite for the inhibition of CYP3A-dependent substrate oxidations by rat liver microsomes and that M2 (and M3, to a lesser extent) may be the active metabolite that can form an inhibitory P450-metabolite complex by CYP3A enzyme(s).

Animals↗

PubMed1998

Linkage between the distribution of mutations in the CYP2C18 and CYP2C19 genes in the Japanese and Caucasian.

1. Two different types of genetic polymorphisms in each of CYP2C18 and CYP2C19 genes were examined and compared with respect to their frequencies in distribution in liver DNA of 39 Japanese and 45 Caucasians. 2. Individuals who were classified into CYP2C19m1 (as detected with SmaI digestion) in exon 5 of CYP2C19 gene were found to display a CYP2C18m1 polymorphism (as detected with DdeI digestion) in the 5'-flanking region of CYP2C18 gene in Japanese and Caucasian populations. The Japanese subjects who were classified into CYP2C19m2 (as detected with BamHI digestion) in exon 4 of CYP2C19 gene were found to have a CYP2C18m2 genetic polymorphism (as detected with Tsp509I digestion) in exon 2 of CYP2C18 gene. None of the Caucasians had the CYP2C18m2 nor CYP2C19m2 alleles. 3. Frequencies in two types (C416T in exon 3, A1061C in exon 7) of CYP2C9 genetic polymorphism were found to be independent to those of CYP2C18 and CYP2C19 genetic polymorphisms in these samples. 4. Thus, the results suggest that the CYP2C18 gene is localized very closely to the CYP2C19 gene on the same human chromosome.

Aryl Hydrocarbon Hydroxylases↗

PubMed1998

Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes.

1. Tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities were determined in liver microsomes of 39 Japanese and 45 Caucasians genotyped for the cytochrome P450 (P450 or CYP) 2C9 gene into three groups, namely the wild-type (Arg144.Ile359), and two heterozygous Cys allele (Cys144.Ile359) and Leu allele (Arg144.Leu359) variants. 2. Good correlations were found between tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities in liver microsomes of Japanese and Caucasians. Humans with the Cys allele CYP2C9 variant, which was detected in 22% of Caucasians, were found to have similar catalytic rates to those of the wild-type in the oxidations of tolbutamide and racemic warfarin, whereas humans with the Leu allele, which was detected in 8% Japanese and 7% Caucasian samples, had lower catalytic rates than those of other two groups. 3. The rates of 6- and 7-hydroxylation of racemic warfarin were correlated well with those of S-warfarin, but not R-warfarin, in human liver microsomes. 4. Both human liver microsomes and recombinant CYP2C9 catalysed 7-hydroxylation of S-warfarin more extensively than those of R-warfarin. K(m)'s for the 7-hydroxylation of S-warfarin were not very different in liver microsomes of humans with these three genotypes. Anti-CYP2C9 antibodies and sulphaphenazole inhibited the 6- and 7-hydroxylation of S-warfarin, but not R-warfarin, by > 90% and the methyl hydroxylation of tolbutamide by about 50%. 5. These results suggest that humans with Leu allele of CYP2C9 have lower Vmax's for S-warfarin 7-hydroxylation and tolbutamide methyl hydroxylation than those with wild-type and Cys allele CYP2C9, although the K(m)'s are not very different in liver microsomes of these three groups of humans. R-warfarin hydroxylation may be catalysed by P450 enzymes other than CYP2C9 in man.

Alleles↗