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T Harauchi

Publications and source records attributed to T Harauchi.

17 recordsLinked to original sources
PubMed2001

Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs.

Both male and female beagle dogs (four dogs/sex) were orally treated with rifampicin (Rif) at the dose of 10 mg/kg/day for 7 days and an additional eight dogs (four dogs/sex) were used as a control. The inducible effect of Rif on intestinal cytochrome P450, especially CYP3A enzyme, was investigated by measuring microsomal testosterone 6beta-hydroxylation (6beta-OHT) activity, immunoblot and ELISA analysis. In male dogs, microsomal 6beta-OHT activity in the duodenum, upper, middle and lower part of the jejunum and the ileum of the control was 229, 204, 194, 129 and 57 pmol/min/mg protein, while the activity of the Rif-treated dogs significantly increased to 456, 486, 430, 192 and 138 pmol/min/mg protein, respectively. The activity of intestinal 6beta-OHT in the control and Rif-treated female dogs showed almost similar levels to those observed in the corresponding male dogs. The activity of intestinal 6beta-OHT in both control and Rif-treated dogs was specifically inhibited by anti-CYP3A12 antiserum. The apparent K(m) value for 6beta-OHT activity in all sections of the small intestine was comparable with that in the liver, and no significant changes were observed in between control and Rif-treated dogs. In both control and Rif-treated dogs, immunoblotting of intestinal microsomes with anti-CYP3A12 antiserum produced a band indistinguishable from that of purified CYP3A12 or of immunoreactive CYP3A12 in liver microsomes. A significant increase in intestinal CYP3A content by Rif treatment was quantitatively verified by the ELISA analysis and the magnitude of its increase correlated well with that of 6beta-OHT activity elevation. Furthermore, the results of immunohistochemistry using the anti-CYP3A12 antiserum indicated that CYP3A protein was specifically distributed in epithelial cells throughout the small intestine and appeared to be predominant at the apical side of villus cells. These results demonstrate that Rif induces not only hepatic CYP3A12 but also intestinal CYP3A in dogs.

Administration, Oral↗
PubMed1998

Characterization of cytochrome P450 (CYP3A12) induction by rifampicin in dog liver.

1. Effects of rifampicin (Rif) on the contents of cytochrome P450 (P450) enzymes (CYP1A1/2, 2B11, 2C21 and 3A12) assessed by enzyme-linked immunosorbent assay and catalytic activities (ethoxyresorufin O-deethylase, and testosterone 6 beta-, 16 alpha- and 16 beta-hydroxylase; 6 beta-, 16 alpha- and 16 beta-OHT) in dog liver microsomes were compared between liver lobes of both the male and female dogs. 2. In the control dogs, the contents of individual P450 enzymes and their activities showed no significant differences between individual liver lobes and between the sexes. 3. Rif treatment (10 mg/kg/day, p.o. for 7 days) induced substantial increases in the content of CYP3A12 and 6 beta- and 16 beta-OHT activities, and slight increases in the content of CYP2B11 and 16 alpha-OHT activity, and their elevated levels were virtually the same between liver lobes. The magnitudes of the elevation of the CYP3A12 level and 6 beta- and 16 beta-OHT activities compared with control levels appeared to be greater in the female dogs. However, the ratios of their magnitudes (CYP3A content/6 beta-OHT activity and CYP3A content/16 beta-OHT activity) showed no differences between the sexes. 4. In both the control and Rif-treated dogs, the activities of 6 beta- and 16 beta-OHT were specifically inhibited by anti-CYP3A12 antiserum, and 16 alpha-OHT activity was specifically inhibited by anti-CYP2B11 and anti-CYP2C21 antiserum. 5. These results indicate that Rif treatment induces the expression of CYP3A12 protein, and correlates well with the elevation of its catalytic activity (6 beta- and 16 beta-OHT), and that the female dog is more responsive to Rif treatment as compared with the male.

Animals↗
PubMed1998

O/W lipid emulsions for parenteral drug delivery. IV. Changes in the pharmacokinetics and pharmacodynamics of a highly lipophilic drug, menatetrenone.

The pharmacokinetics and pharmacodynamics of antihemorrhagic vitamin, menatetrenone after intravenous injection as the lipid emulsion, were compared to those as the micellar solutions. Menatetrenone was selectively delivered to the liver, lungs and spleen and retained in them. Hepatic and splenetic concentration at 6 h (C6h) increased 21.6- and 27.1-fold, respectively, and the area under the tissue concentration-time curve up to 6 h (AUC(0-6h)) were 2.3- and 11.4-fold, respectively, when compared with its micellar solution. Antihemorrhagic effect of menatetrenone was assessed using warfarin-induced hypoprothrombinemic rats. The lipid emulsion of menatetrenone decreased the prothrombin time at 6h after intravenous injection more effectively than micellar solution. The dose response curves indicated that the efficacy of the lipid emulsion was 2.4-2.9 times that of a micellar solution, and this was correlated with AUC(0-6h) rather than C6h. The plasma level of clotting factor VII and the hepatic level of descarboxyprothrombin were also recovered more effectively, while no significant differences were noted between the two formulations for the plasma level of factor II or descarboxyprothrombin at the dose levels examined. Although selective delivery of menatetrenone in the liver by the lipid emulsion was due to phagocytosis by non-parenchymal cells, menatetrenone in the whole liver appeared to contribute to recovery from hypoprothrombinemia.

Analysis of Variance↗
PubMed1995

[Modification of vancomycin nephrotoxicity by other antibiotics in rats].

Vancomycin (VCM) was intravenously administered to rats for 14 days at doses of 150 mg/kg/day and 250 mg/kg/day alone or in combination with 1,000 mg/kg/day of latamoxef (LMOX), flomoxef (FMOX) or cefpirome (CPR) or 250 mg/kg/day of fosfomycin (FOM), and the influences of combined antibiotics on the VCM-induced renal damage were studied. The renal impairment caused by VCM alone was, morphologically, demonstrated mainly as regeneration of tubular epithelium: slight regeneration was observed in a half of rats administered 150 mg/kg/day and slight to extensive regeneration in all the rats administered 250 mg/kg/day. Clinical examinations found apparent increases in urinary LDH and MDH activities in rats administered 250 mg/kg/day, thus showing a good correlation with renal pathological changes. In addition, increase in kidney weight and increase in urinary NAG activity were noted, while changes in plasma urea-N and creatinine were mild, and gamma-GTP activity and protein in urine could not be used as a parameter of the renal impairment. The slight renal impairment as noted in rats administered VCM 150 mg/kg/day alone was not observed at all when LMOX or FMOX was administered concomitantly, and less pronounced even when FOM was administered concomitantly. When CPR was administered concomitantly, the changes were the same as those observed with VCM alone. The renal impairment in rats administered VCM 250 mg/kg/day was apparently less severe when combined with LMOX, FMOX and FOM than that in rats administered VCM alone, and this was supported by apparent reduction of clinical examination values as the parameter of VCM-induced nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of P-450 inducers on glutathione (GSH) depletion by bromobenzene in primary cultures of dog hepatocytes.

Primary cultures of dog hepatocytes sensitivity responded to various inducers of cytochrome P-450; phenobarbital (PB) significantly elevated the activity of 7-ethoxycoumarin O-deethylase (ECOD) and progesterone 6 beta-hydroxylase (6 beta-OHP). beta-Naphthoflavone (beta-NF) and rifampicin (Rif) elevated the levels of 7-ethoxyresorufin O-deethylase (EROD) and 6 beta-OHP, respectively. When primary cultures of dog hepatocytes were incubated with bromobenzene, cellular reduced glutathione (GSH) levels decreased time- and dose-dependently. Pretreatment of the cultures with PB enhanced GSH depletion by bromobenzene, while beta-NF and Rif had little effect, suggesting that the 2B type cytochrome P-450 is responsible for the primary oxidation of bromobenzene to GSH-reactive metabolite(s). Bromobenzene-dependent GSH depletion was completely prevented by 10 microM SKF-525A both in the control and PB-treated primary cultures. Treatment of dog primary cultures with PB analogues also elevated the level of drug-metabolizing activity leading the cells to be more susceptible to GSH depletion by bromobenzene.

Animals↗
PubMed1993

Effects of p-phenylenediamines and adriamycin on primary culture of rat skeletal muscle cells.

In vitro toxicity of p-phenylenediamine derivatives and adriamycin were examined using cultured rat myofibers prepared by the selective plating method, with slight modification. When the myofibers were cultured for 2 days with 100 microM N,N,N',N'-tetramethyl p-phenylenediamine, atrophy and/or swelling of the cells were observed, and the toxic effect was reduced as the number of N-methyl groups in the phenylenediamine molecule was decreased. Adriamycin, at concentrations of greater than 0.25 microM, caused cell injury. Decline of cellular creatine phosphokinase activities generally preceded the apparent morphological changes. The primary culture of rat myofibers responded sensitively to the agents which were myotoxic in vivo.

Animals↗
PubMed1990

A method for determining urinary enzyme activities as nephrotoxic indicators in rats.

A simple, useful method was developed for detecting drug nephrotoxicity in rats. Rat urine excreted by stimulation of the sacral part of the back was collected in a beaker, and enzymes in 0.2 ml of the urine were partially purified by centrifugal ultrafiltration using an Amicon MPS-1 kit. Activities of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), gamma-glutamyltranspeptidase (gamma GTP) and lactate dehydrogenase (LDH), and the protein concentration of the enzyme preparation suspended in phosphate-buffered saline were represented as creatinine ratios. A marked increase in these enzyme activities and protein concentration were observed in rats with kidneys damaged by treatment with cephaloridine, HgCl2, cisplatin or gentamicin. The patterns of increase of these indicators differed with the drug, but in general, LDH showed the highest response and NAG, the longest lasting one. These data agreed with the results reported by other researchers using dialyzed 24-hr urine. Thus, we concluded that this method is an efficient one for determining drug nephrotoxicity in rats.

Acetylglucosaminidase↗
PubMed1989

Depression of liver microsomal vitamin K epoxide reductase activity associated with antibiotic-induced coagulopathy.

Hypoprothrombinemic changes in blood coagulation parameters, such as prolongation of prothrombin time, increase in the level of plasma protein induced by vitamin K absence, and decrease in plasma prothrombin level, were detected in rats fed a vitamin K-deficient diet. These changes were enhanced by the administration of beta-lactam antibiotics containing N-methyltetrazolethiol, thiadiazolethiol or methyl-thiadiazolethiol. Microsomal vitamin K epoxide reductase activity was suppressed with the maximum effect at 1-2 days after the treatment and with recovery, thereafter, gradually to the normal level after 5-7 days. Hypoprothrombinemic alterations in blood coagulation parameters following a single administration of antibiotic to vitamin K-deficient rats were somewhat delayed compared with the change in the epoxide reductase activity, but the effects of the antibiotic on both blood coagulation parameters and the enzyme activity disappeared completely 7 days after the antibiotic treatment. Antibiotic-induced depression of the epoxide reductase activity was observed even in the vitamin K sufficient rats, although the hypoprothrombinemic changes in the blood coagulation parameters did not develop. Vitamin K administration could normalize the blood coagulation parameters in the hypoprothrombinemic rats caused by treatment with the antibiotics but without recovery of the decreased epoxide reductase activity. These results suggest that some antibiotics inhibit liver microsomal vitamin K epoxide reductase, which causes hypoprothrombinemia to develop under vitamin K-deficient conditions.

Animals↗
PubMed1988

In vivo effects of beta-lactam antibiotics and heterocyclic thiol compounds on vitamin K-dependent carboxylation activity and blood coagulation factors in vitamin K-deficient rats.

The in vivo effects of heterocyclic thiol compounds, corresponding to the 3'-position substituents of several beta-lactam antibiotics, on blood coagulation factors and on liver microsomal gamma-glutamylcarboxylation (gamma-carboxylation) activity were evaluated in rats maintained on a vitamin K-deficient diet. These rats, when compared to normal control animals, exhibited hypoprothrombinemic changes: prolongation of both prothrombin time and activated partial thromboplastin time, decreases in factor VII and plasma prothrombin, and increases in PIVKA II (descarboxyprothrombin) both in plasma and liver. They also displayed a marked increase in liver microsomal gamma-carboxylation activity. These blood coagulation variables could be altered markedly by administering various heterocyclic thiol compounds to the vitamin K-deficient rats, although these compounds did not inhibit gamma-carboxylation activity in an assay system using phylloquinone. A similar pattern of alteration was observed when some beta-lactam antibiotics were administered. Increased microsomal gamma-carboxylation activity in antibiotic-treated vitamin K-deficient rats was normalized by the administration of vitamin K, concomitant with the recovery of blood coagulation variables to the normal range. The results indicate that antibiotic-induced hypoprothrombinemia in vivo is not caused by inhibition of enzymes of the gamma-carboxylation system, such as vitamin K reductase and gamma-glutamylcarboxylase, but is related to the endogenous vitamin K level.

Animals↗
PubMed1988

Assessment of L-ascorbic acid requirement for prolonged survival in ODS rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Assessment of L-ascorbic acid requirement for prolonged survival in ODS (genotype: od/od) rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were examined. In ODS rats without L-ascorbic acid synthesizing ability, the 50 ppm dietary total ascorbic acid (TAA) was insufficient to survive for 4 weeks, the 250 ppm dietary TAA was sufficient to survive for 36 weeks. In examination of BBN treatment, ODS rats--although showing a lower availability of TAA than the heterozygotes (+/od) and normal (+/+) rats with L-ascorbic acid synthesizing ability--were equally susceptible to bladder carcinogenesis.

Animals↗
PubMed1988

Vitamin K-reversible hypoprothrombinemia in rats. I. Sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.

Male and female rats were fed an ordinary diet which contained about 500 ng vitamin K/g or a vitamin K-deficient diet containing less than 5 ng vitamin K/g. Hypoprothrombinemic changes such as prolongation of the prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected in male rats within 4-6 days after feeding of the vitamin K deficient diet. Blood clotting factor VII and descarboxy prothrombin (PIVKA) levels changed rapidly, with maximum alteration at 2-4 days. Similar changes in factor VII and PIVKA levels were observed in female rats, but they appeared only after feeding of the K deficient diet for a long period. PT and APTT in female rats showed slight or no alteration even after 10 day feeding of the K-deficient diet. These results indicate that male rats are more susceptible to vitamin K deficiency than female rats. Administration of latamoxef led to a dose-dependent development of hypoprothrombinemia in vitamin K-deficient female rats. The hypoprothrombinemia in vitamin K-deficient female rats was caused by beta-lactam antibiotics with N-methyltetrazolethiol, thiadiazolethiol and methyl-thiadiazolethiol as the 3'-position substituent of the cephem nucleus.

Animals↗
PubMed1986

Effects of vitamin K-deficient diets and fasting on blood coagulation factors in conventional and germ-free rats.

Feeding of vitamin K-deficient diets or fasting produced vitamin K deficient syndromes in both conventional and germ-free male rats in 3 days, increasing prothrombin time (PT), activated partial thromboplastin time (APTT), plasma and liver descarboxyprothrombin (PIVKA) levels and liver gamma-glutamylcarboxylase activities, but decreasing plasma clotting factor VII and prothrombin levels. These changes were not found when daily 30 micrograms/rat of vitamin K1 was injected during this period. The changes caused by fasting were comparable with those caused by a diet containing 20-30 ng/g of vitamin K1, while a diet containing less than 5 ng/g caused greater changes in both conventional and germ-free rats. Germ-free rats on a diet containing sufficient amounts of vitamin K1 showed PT and APTT values similar to those in conventional rats, but lower plasma clotting factor levels and higher PIVKA and microsomal gamma-glutamylcarboxylase activities. The values for PT, APTT, factor VII, prothrombin and PIVKA in the fasted germ-free rats were almost the same as those in the fasted conventional rats. These findings suggest that menaquinones synthesized in the large intestine are not utilized sufficiently to prevent vitamin K deficiency in rats.

Animals↗
PubMed1986

Liver and plasma levels of descarboxyprothrombin (PIVKA II) in vitamin K deficiency in rats.

Descarboxyprothrombin (PIVKA II) is a precursor of prothrombin without biological activity, and it increases with vitamin K deficiency. We studied the time course changes in liver and plasma levels of PIVKA II during the progress of vitamin K deficiency in rats. Good correlation was observed between liver PIVKA II and plasma PIVKA II and between liver or plasma PIVKA II and plasma prothrombin in experiments in which rats were fed a vitamin K-deficient diet. Feeding of a vitamin K-deficient diet or fasting caused marked increases in liver and plasma PIVKA II in male rats and a weaker response in female rats. Warfarin, a vitamin K antagonist, caused an abrupt increase in liver PIVKA II, but the increase in plasma PIVKA II was delayed about 3 hr. Plasma prothrombin decreased from about 30 min later. Factor VII decreased similarly to prothrombin, and changes in the prothrombin time and activated partial thromboplastin time were slower than the changes in these substances. Sex differences were not seen in these warfarin actions. These observations indicate that liver and plasma PIVKA II are sensitive markers of vitamin K deficiency in rats, and assay of PIVKA II can be useful for analyzing the action mechanism of drugs which influence blood coagulation.

Animals↗
PubMed1985

Effect of sex hormones on hypoprothrombinemia induced by N-methyltetrazolethiol in rats.

N-Methyltetrazolethiol (NMTT) increased prothrombin time (PT) and decreased plasma factor VII and prothrombin levels only in vitamin K-deficient male rats. In female rats identical treatment with NMTT did not produce hypoprothrombinemia. Conventional and germ-free rats displayed no significant difference in the manifestation of hypoprothrombinemia, but the increase of PT in NMTT-treated vitamin K-deficient rats was greater in the germ-free males. Estradiol administration or castration of male rats retarded manifestation of vitamin K deficient syndromes such as increases of PT and activated partial thromboplastin time (APTT), decreases of plasma factor VII and prothrombin levels, and increases of plasma and liver descarboxyprothrombin (PIVKA) levels, and testosterone injection to the castrated rats restored these changes. In female rats testosterone treatment or castration enhanced the manifestation of hypoprothrombinemia and estradiol treatment to the castrated females retarded it. Gamma-glutamyl-carboxylase activity was increased by vitamin K-deficiency but not inhibited by testosterone or NMTT. These data suggest that estrogen protects the rat against manifestation of hypoprothrombinemia even with NMTT treatment, while androgen enhances vitamin K deficiency, and supplementation of vitamin K prevents its deficiency in NMTT-treated rats.

Animals↗
PubMed1984

A rat mutant unable to synthesize vitamin C.

A colony of Wistar rats with a hereditary defect in L-ascorbic acid-synthesizing ability was established. This rat, like primates and guinea pigs, lacks L-gulonolactone oxidase (EC 1.1.3.8) which catalyzes the last step of L-ascorbic acid biosynthesis. When L-ascorbic acid was added to their drinking water, the rats grew almost normally and were fertile. These mutant rats should be useful not only for nutritional and pharmacological studies on vitamin C, but also for genetic studies on the lack of this enzyme.

Animals↗
PubMed1982

Ontogeny of thyroid peroxidase activity in perinatal rats.

The ontogeny of thyroid peroxidase (TPO) activity was investigated in rat foetuses and neonates. From day 19 to 22 of gestation in intact pregnant rats, the TPO activity in their foetuses increased with foetal age. Following maternal treatment with propylthiouracil (PTU), the TPO activity markedly increased in foetuses on and after day 20 of gestation. The TPO activity in encephalectomized foetuses increased as markedly as that in intact littermates, whereas that in hypophysectomized littermates failed to increase. Newborn rats nursed by mothers treated with PTU had a TPO activity similar to that in controls of untreated mothers. There was also no difference in the TPO activity between hypophysectomized adult females and intact adult ones. These observations show that in foetal rats, TPO activity increases disproportionately to the thyroid weight, but not in newborn and adult rats, and suggest that preferential synthesis of this enzyme occurs in addition to cell hypertrophy during foetal life.

Animals↗