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T Kamataki

Publications and source records attributed to T Kamataki.

At least 145 records · Page 8Linked to original sources
PubMed1994

Stereoselective S-oxidation of flosequinan sulfide by rat hepatic flavin-containing monooxygenase 1A1 expressed in yeast.

Rat hepatic flavin-containing monooxygenase (FMO) 1A1 expressed in yeast catalysed the S-oxidation of flosequinan sulfide (7-fluoro-1-methyl-3-methylthio-4-quinolone) to R(+)-flosequinan (sulfoxide form, R(+)-7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone) but not to S(-)-flosequinan, and did not catalyse the oxidation of R(+)- and S(-)-flosequinan to flosequinan sulfone. The Km and Vmax for the stereoselective S-oxidation were 33 microM and 6.2 nmol per min per mg of microsomal protein, respectively. The S-oxidation was inhibited by 1-(1-naphthyl)-2-thiourea and thiobenzamide. n-Octylamine activated the S-oxidation with little change in stereoselectivity. The ability of the recombinant yeast to produce R(+)-flosequinan from flosequinan sulfide could be maintained for at least 2 days and exemplifies the value of a recombinant yeast expressing FMO as a stereoselective bioreactor.

Animals↗
PubMed1994

Molecular cloning and sequence analysis of hamster CYP2E1.

Two cDNA clones, pHSj31 and pHSj3, coding for CYP2E1 were isolated from a hamster liver cDNA library. The sequence analyses revealed that they encoded the same polypeptide of 493 amino acid residues (M(r) = 56,616) and differed from the length of their 3'-untranslated region. The deduced amino acid sequence of hamster CYP2E1 showed approx. 90% identities with those of the rats and mice, and approx. 80% identities with those of the rabbits, monkeys and humans. The NH2-terminal 35 deduced amino acid sequences of hamster CYP2E1 were completely identical with purified protein, ha P-450j. The Northern blot analysis showed that CYP2E1 was expressed in livers and to lesser extents in kidneys and lungs.

Amino Acid Sequence↗
PubMed1994

Activities of drug-metabolizing enzymes in the liver of Suncus murinus: possible lack of N-acetyltransferase activity in liver cytosol.

The amounts of several drug-metabolizing enzymes in livers of Suncus murinus (suncus) were studied in comparison with rats. The content of cytochrome P450 in suncus was less than one third that seen in rats. Activities of glutathione S-transferase, UDP-glucuronyltransferase and arylhydroxycarbon hydroxylase in suncus were less than half those in rats. Activity of flavin-containing monooxygenase in suncus was 71% that of rats. Interestingly, N-acetyltransferase (NAT) activity in suncus liver cytosols was not detectable: no detectable activities were seen with aniline, p-aminobenzoic acid and p-amino-salicylic acid as substrates. We propose that suncus is a unique animal possibly lacking NAT in liver cytosol.

Animals↗
PubMed1994

Occurrence of autoantibody to protein disulfide isomerase in rats with xenobiotic-induced hepatitis.

The occurrence of an autoantibody to protein disulfide isomerase (PDI) in rats after administration of various hepatotoxic drugs was investigated by immunoblotting and radioimmunoassay. An anti-PDI autoantibody was detected with high frequency in rats treated with D-galactosamine, acetaminophen with diethylmaleate, and carbon tetrachloride with diethylmaleate. The antibody-positive rate was relatively low in the groups of rats given carbon tetrachloride, acetaminophen or DL-ethionine alone. The anti-PDI antibody was not detected in rats treated with diethylmaleate alone. Although the mechanism of the production of the anti-PDI autoantibody is unclear, the occurrence of anti-PDI antibody correlated with high serum GPT activities. It is suggested that the autoantibody plays an important role in the development and persistence of drug-induced hepatitis.

Alanine Transaminase↗
PubMed1994

Occurrence of autoantibody to protein disulfide isomerase in patients with hepatic disorder.

The occurrence of autoantibody to protein disulfide isomerase (PDI) was examined in sera from patients with alcoholic liver disease, liver cirrhosis, systemic lupus erythmatosus (SLE) and cancer. Judging by results of Western blotting using a purified preparation of PDI, the anti-PDI antibody was hardly seen in most sera from healthy controls but was raised in patients with alcoholic liver disease, liver cirrhosis, SLE and liver cancer. When the antibody titer to PDI was measured by radioactivity in a radioimmunoassay, positive values (cut off value; mean + 2SD = 256 cpm) were seen in 46% (11/24) of the patients with moderate alcoholic liver disease (mean radioactivity, 339 cpm) and in 54% (7/13) of those with severe alcoholic liver disease (mean radioactivity, 664 cpm). Only 8% (4/48) of the healthy controls were positive (mean radioactivity, 50 cpm). Four of six patients with hepatoma were positive, while none of the seven patients with non-hepatic cancer were positive. The positive proportions in the patients with liver cirrhosis and SLE were 64% (9/14) and 40% (4/10), respectively. These results suggest that the occurrence of anti-PDI antibody would play an immunological role in the progression of hepatic disorders.

Adult↗
PubMed1994

Stereoselective pharmacokinetics and interconversions of flosequinan enantiomers containing chiral sulphoxide in rat.

1. In order to study the pharmacokinetics of flosequinan enantiomers ((+-)-7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) containing chiral sulphur, plasma levels of (+)-(R)- and (-)-(S)-flosequinan (R-FSO and S-FSO) and two metabolites (flosequinan sulphide (FS) and flosequinan sulphone (FSO2)) were measured after oral and i.v. administration of racemic flosequinan (rac-FSO), R-FSO and S-FSO in male rat. 2. The pharmacokinetic parameters of the enantiomers were different after oral and i.v. administration of R-FSO and S-FSO. The plasma clearance of R-FSO was higher than S-FSO. 3. The major metabolites of boh R-FSO and S-FSO was FSO2. A minor metabolite, FS, was also detected in plasma. 4. Interconversions occurred after the oral and i.v. administration of R-FSO and S-FSO. The amount of interconversion from S-FSO and R-FSO was greater than that from R-FSO to S-FSO. The rate of interconversion after oral administration was higher than that after i.v. administration. 5. After i.v. administration of FS, R-FSO and S-FSO were detected in plasma, suggesting that the interconversion occurred via formation of FS. 6. The pharmacokinetic parameters of R-FSO after administration of rac-FSO differed from that after administration of R-FSO, indicating the interaction between each enantiomer.

Administration, Oral↗
PubMed1994

Effects of cyclosporin-A and D-penicillamine on the development of hepatitis and the production of antibody to protein disulfide isomerase in LEC rats.

Long Evans Cinnamon (LEC) rats, which spontaneously develop hepatitis, produce an autoantibody to protein disulfide isomerase (PDI) before the development of clinical signs of hepatitis. Anti-PDI antibody may be associated with immunological hepatitis. Thus, the purpose of this study was to investigate the effects of some drugs on the development of hepatitis and the occurrence of the antibody in LEC rats. Cyclosporin-A, an immunosuppressant, and D-penicillamine, which promotes copper excretion, were orally administered to LEC rats for 23 weeks. Mortality, blood biochemical parameters and the titer of serum anti-PDI antibody were measured. In control LEC rats, four of eight rats died before 20-weeks-old. Only one of seven rats in the cyclosporin-A-treated group died at the age of 20 weeks. When rats were treated with D-penicillamine, the development of clinical signs of hepatitis was inhibited, and all rats survived. Cyclosporin-A-treated rats showed increases in blood biochemical parameters similar to those in control rats. The titer of anti-PDI antibody in control rats was higher the non-survivors than survivors. These findings suggest the association of the anti-PDI antibody with lethality, but not with the apparent development and progression of hepatitis as measured by blood biochemical parameters in LEC rats.

Administration, Oral↗
PubMed1994

[Preventive effect of TJ-14, a kampo (Chinese herb) medicine, on diarrhea induced by irinotecan hydrochloride (CPT-11)].

Diarrhea is one of dose-limiting factors of irinotecan (CPT-11) and its incidence is over 60% in patients receiving this drug. Therefore, it is important to prevent diarrhea for more effective use of CPT-11. We used Hange-shashinto (TJ-14), an ethical Kampo (Chinese herb) Medicine, to prevent diarrhea induced by CPT-11. Twenty-three patients (9 lung cancer, 4 pancreatic cancer, 2 colorectal cancer, 4 malignant lymphoma, and 4 other types of cancer) entered in this study. All patients were treated with CPT-11 in combination with oral TJ-14 (7.5 g t.i.d.) every day starting prior to CPT-11 infusion. The dose of CPT-11 was 60-100 mg/m2/w, 120-150 mg/m2/2 w or 40 mg/m2/d x 3 days/w. Three of 23 patients could not evaluate the efficacy and safety of TJ-14 since they could not take TJ-14 due to its odor and taste. The efficacy and safety of TJ-14 was not evaluated in one patient also since the patient could not continue taking TJ-14 due to vomiting induced by CPT-11. Nine patients showed an excellent response (no diarrhea or only 1 day of ECOG Grade 1 diarrhea). 9 showed a good response (Grade 1 diarrhea that disappears within 3 days) and one did not reveal response. It is suggested that TJ-14 possesses a preventive effect against diarrhea induced by CPT-11.

Administration, Oral↗
PubMed1994

Sex-related differences in the expression of cytochrome P450 in hamsters: cDNA cloning and examination of the expression of three distinct CYP2C cDNAs.

Sex-related differences in the expression of cytochrome P450 isozymes in hamsters were investigated. Three distinct cDNA clones (assigned as CYP2C25, CYP2C26, and CYP2C27) were isolated from liver cDNA libraries from male and female hamsters, using rat CYP2C11 cDNA as a probe. Sequence analysis revealed that these three forms were very similar to each other (> 90% identity of nucleotide sequences) and belong to the CYP2C gene subfamily. The CYP2C25, CYP2C26, and CYP2C27 cDNA clones consisted of an open reading frame encoding 490 amino acids. CYP2C25, CYP2C26, and CYP2C27 proteins expressed in Saccharomyces cerevisiae catalyzed the hydroxylation of tolbutamide and the N-demethylation of aminopyrine and benzphetamine. Only CYP2C25 showed testosterone hydroxylase (16 beta) activity. Northern blot analyses with specific oligonucleotide probes demonstrated that expression of CYP2C27 was male specific and male predominant in kidneys and livers, respectively. No sex-related difference was observed in the expression of CYP2C25 and CYP2C26. These results support our previous findings that sex-related differences in the expression of liver microsomal cytochromes P450 occur in hamsters.

Aminopyrine↗
PubMed1993

Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control.

CYP3 A4 is the adult-specific form of cytochrome P450 in human livers [Komori, M., Nishio, K., Kitada, M., Shiramatsu, K., Muroya, K., Soma, M., Nagashima, K. & Kamataki, T. (1990) Biochemistry 29, 4430-4433]. The sequences of three genomic clones for CYP3A4 were analyzed for all exons, exon-intron junctions and the 5'-flanking region from the major transcription site to nucleotide position -1105, and compared with those of the CYP3A7 gene, a fetal-specific form of cytochrome P450 in humans. The results showed that the identity of 5'-flanking sequences between CYP3A4 and CYP3A7 genes was 91%, and that each 5'-flanking region had characteristic sequences termed as NFSE (P450NF-specific element) and HFLaSE (P450HFLa specific element), respectively. A basic transcription element (BTE) also lay in the 5'-flanking region of the CYP3A4 gene as seen in many CYP genes [Yanagida, A., Sogawa, K., Yasumoto, K. & Fujii-Kuriyama, Y. (1990) Mol. Cell. Biol. 10, 1470-1475]. The BTE binding factor (BTEB) was present in both adult and fetal human livers. To examine the transcriptional activity of the CYP3A4 gene, DNA fragments in the 5'-flanking region of the gene were inserted in front of the simian virus 40 promoter and the chloramphenicol acetyltransferase structural gene, and the constructs were transfected in HepG2 cells. The analysis of the chloramphenicol acetyltransferase activity indicated that (a) specific element(s) which could bind with a factor(s) in livers was present in the 5'-flanking region of the CYP3A4 gene to show the transcriptional activity.

Adult↗
PubMed1993

Identification of protein disulfide isomerase and calreticulin as autoimmune antigens in LEC strain of rats.

Long Evans Cinnamon (LEC) rats, showing spontaneous hereditary hepatitis and hepatic carcinoma, were found to possess autoimmune antibodies to liver microsomal proteins, particularly to proteins with the molecular weight of 56kD and 55kD. The antibodies occurred in association with acute lethal hepatitis in the LEC rats in our previous study. Two-dimensional immunoblot analysis of the antigenic proteins revealed that the 56kDa and 55kDa proteins showed 4.2 and 4.0 pI values and were estimated to be protein disulfide isomerase (PDI) and calreticulin, respectively, from NH2-terminal amino acid sequence analysis. These proteins were further identified by immunoblot analyses using purified proteins and specific antibodies. PDI was a major autoimmune antigenic protein.

Amino Acid Sequence↗
PubMed1993

Rat liver flavin-containing monooxygenase (FMO): cDNA cloning and expression in yeast.

A rat liver cDNA clone, RFMO1, coding for a flavin-containing monooxygenase (FMO) was isolated. This cDNA clone encoded a protein of 532 amino acids. The deduced amino acid sequence was 84, 82 and 82% identical to those of the pig, human (Form 1) and rabbit (Form 1) liver FMOs, while it was only 52, 50, 54, 56 and 54% identical to the human (Form II), human (Form 2) and rabbit liver FMOs (Form 2) and rabbit and guinea pig lung FMOs. RNA blot analysis showed that rat liver FMO was also expressed in lung and kidney and to a lesser extent in the heart and brain. An expression plasmid, pAMFMO, was constructed and the FMO protein expressed in yeast (AH22). This FMO protein catalyzed thiobenzamide S-oxidation, and NADPH oxidation associated with the S- or N-oxidation of thiourea, N,N-dimethylaniline, trimethylamine, imipramine, chlorpromazine, N,N-dimethylhydrazine, thioacetamide as substrates. The S-oxidation activities of thiobenzamide and thiourea were enhanced by n-octylamine, a known enhancer of FMO, and inhibited by alpha-naphthylthiourea, a known inhibitor of FMO. This is the first report in which FMO with catalytic activities was stably expressed.

Amines↗
PubMed1993

Characterization of specific cytochrome P450 enzymes responsible for the metabolism of diazepam in hepatic microsomes of adult male rats.

The role of several P450 enzymes in the metabolism of diazepam (DZ) has been investigated. Hepatic microsomes of adult male rats were pretreated with antisera raised against the P450s CYP3A2, 2B1, 2C6, 2C11, 2D1 and 2E1, and their influence on the subsequent metabolism of DZ was determined by simultaneously measuring the changes in the relative rates of formation of its metabolites. Several forms of P450 were found to be positively involved in DZ metabolism. Antisera of the "male-specific" P450 enzyme CYP2C11 partially inhibited both DZ N-demethylase and C3 hydroxylase activities (60%) which resulted in decreased formations of N-desmethyl-DZ (NDZ) and 3-hydroxy-DZ (3HDZ), respectively. In a reconstitution experiment with the purified enzyme, CYP2C11 predominantly catalysed the formation of NDZ from DZ. Antisera of a further male-specific P450 CYP3A2 strongly inhibited (95%) the C3 hydroxylase of DZ and thus 3HDZ formation. A corresponding reconstitution experiment with this same P450 enzyme gave 3HDZ as principal product. CYP2D1 antisera inhibited the aromatic hydroxylation of DZ (98%) and subsequent formation of 4'-hydroxy-DZ (4'HDZ). This enzyme was also observed to inhibit DZ N-demethylase activity (60%). A reconstitution experiment with pure CYP2D1 catalysed the formation of both 4'HDZ and NDZ.

Animals↗