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Biomedical subjects

T Watabe

Publications and source records attributed to T Watabe.

At least 127 records · Page 7Linked to original sources
PubMed1985

A reactive hydroxymethyl sulfate ester formed regioselectively from the carcinogen, 7,12-dihydroxymethylbenz[alpha]anthracene, by rat liver sulfotransferase.

The carcinogen, 7,12-dihydroxymethylbenz[alpha]anthracene (DHBA), was regioselectively conjugated in the presence of 3'-phosphoadenosine 5'-phosphosulfate by male rat liver cytosolic sulfotransferase to DHBA 7-sulfate. The sulfate ester was highly reactive and showed a potent, intrinsic mutagenicity toward Salmonella typhimurium TA 98.

Animals↗
PubMed1985

The obligatory intermediacy of 16,17 alpha- and 16,17 beta-epoxides in the biotransformation of androsta-5,16-dien-3 beta-ol to androst-5-ene-3 beta, 16 alpha, 17 beta- and -3 beta, 16 beta, 17 alpha-triols by male rat liver microsomes.

The C16-double bond of the biolefinic steroid, androsta-5,16-dien-3 beta-ol (delta 16-ANDO), was regioselectively oxidized by male rat liver microsomes in the presence of NADPH and EDTA to 16 alpha, 17 alpha-epoxyandrost-5-en-3 beta-ol (delta 16-ANDO 16,17 alpha-epoxide), 16 beta,-17 beta-epoxyandrost-5-en-3 beta-ol (delta 16-ANDO 16,17 beta-epoxide), androst-5-ene-3 beta, 16 alpha, 17 beta-triol (delta 16-ANDO 16 alpha, 17 beta-glycol), and androst-5-ene-3 beta, 16 beta, 17 alpha-triol (delta 16-ANDO 16 beta, 17 alpha-glycol). The microsomes hydrolyzed delta 16-ANDO 16,17 alpha-epoxide specifically to the 16 beta, 17 alpha-glycol and delta 16-ANDO 16,17 beta-epoxide to the 16 beta, 17 alpha-glycol and the 16 alpha, 17 beta-glycol in an equal ratio. delta 16-ANDO 16,17 alpha-epoxide was much more susceptible to microsomal hydrolysis than the 16,17 beta-epoxide. The xenobiotic epoxide hydrolase inhibitor, 3,3,3-trichloropropene 1,2-oxide, potently inhibited microsomal hydrolysis of delta 16-ANDO 16,17-epoxides as well as of benzo[a]pyrene 4,5-epoxide and styrene 7,8-epoxide. Addition of 3,3,3-trichloropropene 1,2-oxide accumulated the 16,17-epoxides formed from delta 16-ANDO in the reaction medium with concomitant decrease in the amounts of the 16,17-glycols formed, leading to a conclusion that the 16,17-epoxides played a role as obligatory intermediates in the microsomal delta 16-oxidation of delta 16-ANDO to the 16,17-glycols. Epoxidation of delta 16-ANDO was stereoselectively mediated by a cytochrome P-450 with quite unique properties to form the 16,17 alpha-epoxide as the major oxidation product and the 16,17 beta-epoxide as the minor. The epoxidation was strongly inhibited with CO, activated with 2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride more than twice as much, and little affected with metyrapone and 7,8-benzoflavone. A pretreatment of the animals with 3-methylcholanthrene induced the delta 16-ANDO-epoxidizing activity of their microsomes 1.5 times higher than those from the control animals. However, a pretreatment with phenobarbital reduced the enzyme activity to one-half of the control microsomes. Under the same conditions, microsomal activities of hydroxylation of benzo[a]pyrene and N-demethylation of benzphetamine were significantly induced by the pretreatments with 3-methylcholanthrene and phenobarbital, respectively.

Androstenols↗
PubMed1985

Enantioselectivity in glutathione conjugation of 1,2-epoxy-1,2,3,4-tetrahydronaphthalene by hepatic glutathione S-transferase.

Enantiomers of 1,2-epoxy-1,2,3,4-tetrahydronaphthalene (ETN) were conjugated with glutathione (GSH) specifically at their benzylic oxiran carbons, with a marked difference in rate [(1R,2S)-(+)- less than (1S,2R)-(-)-ETNs] as well as in affinity for GSH S-transferase [Km: (1S,2R)-(-)- less than (1R, 2S)-(+)-ETNs], in rat liver cytosol to yield two diastereomeric S-(2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl)glutathiones which were separable by reverse partition hplc. Enzymatic GSH conjugation of racemic ETN occurred preferentially with the (1S,2R)-(-)-component as a result of its retarding effect on the conjugation of the (1R,2S)-(+)-counterpart, one half of which remained in enantiomerically pure form in the incubation medium when the (1S,2R)-(-)-component had been completely conjugated.

Animals↗
PubMed1985

Nonsurgical retrieval of an accidentally dislodged vent catheter retention ring.

During open mitral commissurotomy in a patient with mitral stenosis, a vent catheter retention ring was accidentally slipped off into the left atrium and lodged near the orifice of the right renal artery. Nonsurgical retrieval of this intraarterial foreign body was performed successfully under fluoroscopic guidance in the operating room using a combined approach of angiographic catheters and guidewire, these being inserted via the arteriotomy site of the right femoral artery created for cardiopulmonary bypass.

Catheterization↗
PubMed1985

Effect of liver S9 from 3,4,5,3',4'-pentachlorobiphenyl-pretreated rats on the mutagenic activity of the various carcinogens toward Salmonella typhimurium TA 98.

Effects of liver 9000 X g supernatant fraction from 3,4,5,3',4'-pentachlorobiphenyl- and 2,4,5,2',4',5'-hexachlorobiphenyl-pretreated rats (PenCB-S9 and HexCB-S9, respectively) on the mutagenic activities of well-known carcinogens, benzo-[a]pyrene (BP), Glu-P-1 (2-amino-6-methyldipyrido [1,2-a:3',2'-d]imidazole), Trp-P-1 (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole), and aflatoxin B1 (AFB), toward Salmonella typhimurium TA 98 have been described. Although the mutagenic activities of all of these carcinogens were enhanced by these S9, PenCB-S9 especially highly activated BP, Glu-P-1, and Trp-P-1. The ability of PenCB-S9 to activate the carcinogens was much higher than that of liver 9000 X g supernatant fraction from 3-methylcholanthrene-pretreated rats (MC-S9). PenCB-S9 enhanced the mutagenic activity of BP 8 times higher than MC-S9, while Glu-P-1 and Trp-P-1 were activated by PenCB-S9 twice as much as by MC-S9. Effect of HexCB-S9 on the mutagenic activities of the above-mentioned three carcinogens was much less than those of PenCB- and MC-S9 and a little higher than that of 9000 X g supernatant fraction from rats pretreated with phenobarbital. As for AFB, phenobarbital was the most potent inducer, and HexCB and PenCB were next to this. Data suggest that PenCB is a strong inducer of P-448 species which activate environmental toxicants.

Aflatoxin B1↗
PubMed1985

Responses of plasma adrenocorticotropin and cortisol to intravenous injection of synthetic ovine corticotropin releasing factor in the morning and early evening in normal human subjects.

This study was designed to compare the responsiveness of adrenocorticotropin (ACTH) and cortisol secretion to corticotropin-releasing factor (CRF) in the morning and early evening in normal human subjects. Synthetic ovine CRF (1.0 micrograms/kg) or normal saline, was administered as an i.v. bolus injection to six normal males at 900 h and 1700 h. Blood samples were obtained before and 15, 30, 60, 90 and 120 min after CRF or saline injection. Significant increases in plasma ACTH and cortisol levels were observed in all subjects at the both time of testing after CRF injection. The net increments in the areas under the concentration curve (areas in the CRF experiment minus those in the saline control experiment) were not statistically different for both ACTH (mean +/- SEM: 41.0 +/- 10.6 pg/ml h in the morning: 51.1 +/- 8.9 pg/ml h in the evening) and cortisol (mean +/- SEM: 28.5 +/- 5.0 micrograms/dl h in the morning; 36.2 +/- 4.0 micrograms/dl h in the evening). Also no significant difference was observed in net increment, peak level and the ratio of peak level to the basal level of ACTH and cortisol after CRF injection. There were no appreciable changes in plasma concentrations of growth hormone, thyroid-stimulating hormone or prolactin, although slight but statistically significant rises in plasma levels of luteinizing hormone and follicle-stimulating hormone were observed. These results suggest that there is no significant difference in responsiveness of the pituitary-adrenal axis to CRF in the morning (900 h) and early evening (1700 h), and thus the time of day will not necessarily have to be considered when CRF is used between these times in a clinical test to evaluate pituitary ACTH reserve.

Adrenocorticotropic Hormone↗
PubMed1985

Sulfate esters of hydroxymethyl-methyl-benz[a]anthracenes as active metabolites of 7,12-dimethylbenz[a]anthracene.

7-Hydroxymethyl-12-methylbenz[a]anthracene (7-HMBA) and 12-hydroxymethyl-7-methylbenz[a]anthracene (12-HMBA), carcinogenic major metabolites of 7,12-dimethylbenz[a]anthracene (DMBA) in untreated rat liver, showed high mutagenic activities toward Salmonella typhimurium TA 98 after preincubation with a sulfotransferase-PAPS system consisting of ATP, sodium sulfate, and a post-mitochondrial fraction (S-9) or a soluble supernatant fraction (S-105) from untreated rat liver. The 7- and 12-HMBAs themselves induced His+ mutation in TA 98 only slightly after preincubation with S-9 in the presence of an NADPH-generating system. Mutagenicity of DMBA toward TA 98 after preincubation with S-9 in the presence of the NADPH-generating system was remarkably enhanced by the addition of ATP and sodium sulfate. The active metabolites, 7-HMBA sulfate and 12-HMBA sulfate, were isolated from these preincubation systems and identified by comparison with the corresponding synthetic specimens. The sulfuric acid ester conjugates were potent mutagens toward TA 98 in the absence of rat liver subcellular fractions. The conjugates bound covalently at significant rates to calf-thymus DNA as well as to S-105 proteins at 37 degrees and pH 7.4 through the 7- or 12-methylene carbon with concomitant loss of their sulfate group. In the presence of S-105, glutathione inhibited the mutagenicity of the metabolically formed or exogenously added 7- and 12-HMBA sulfates. The non-mutagenic glutathione conjugates were isolated from the incubation mixtures and identified as S-(12-methylbenz[a]anthracen-7-yl)methylglutathione from 7-HMBA or its sulfate and S-(7-methylbenz[a]anthracen-12-yl)methylglutathione from 12-HMBA or its sulfate.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Regiospecific and diastereoselective inactivation of mutagenic 9,10-dihydrobenzo[a]-pyrene 7,8-oxide by hepatic cytosolic glutathione S-transferase.

Racemic, (7R,8S)-(+)-, and (7S,8R)-(-)-9,10-dihydrobenzo[a]pyrene 7,8-oxides (DBPOs) showed markedly different mutagenicity towards Salmonella typhimurium TA 98 in the order of (7R,8S)-(+)- greater than racemic greater than (7S,8R)-(-)-DBPOs. The enantiomeric epoxides were inactivated at significantly different rates by preincubating with rat liver cytosol fortified with glutathione (GSH) in the order of (7S,8R)-(-)- greater than racemic greater than (7R,8S)-(+)-DBPOs. Two non-mutagenic water-soluble metabolites were isolated from the preincubation mixture containing racemic DBPO as a substrate, separated by hplc, and identified by 13C nmr and uv absorption spectroscopy as diastereoisomers of S-(8-hydroxy-7,8,9,10-tetrahydrobenzo[a]pyren-7-yl)glutathione (conjugates I and II). Conjugates I and II were specifically yielded from (7R,8S)-(+)- and (7S,8R)-(-)-DBPOs, respectively, at different rates by rat liver cytosol; apparent values of Km were 20.1 and 15.6 microM and of Vmax 17.2 and 26.7 nmole/mg protein/min for (7R,8S)-(+)- and (7S,8R)-(-)-DBPOs, respectively. Conjugates I and II, therefore, were reasonably assigned to have (7S,8S)- and (7R,8R)-configurations, respectively. Conjugate II was yielded preferentially to conjugate I from racemic DBPO at an early stage of the enzyme reaction.

Animals↗
PubMed1984

A mechanism for epoxidation of cholesterol by hepatic microsomal lipid hydroperoxides.

Evidence was obtained, using cis-stilbene as a model substrate, for the participation of peroxy and/or oxy radicals in epoxidation of cholesterol by rat liver microsomal phospholipid hydroperoxides and a ferrous ion-ADP complex. Under the conditions used, cholesterol was epoxidised to the alpha- and beta-epoxides in the ratio 1:2-4, and cis-stilbene to trans-stilbene oxide without concomitant formation of the cis-oxide. Microsomal phospholipid hydroperoxides could be replaced with methyllinoleate monohydroperoxide for the epoxidation of both substrates. The hydroperoxide-mediated epoxidations were completely inhibited by alpha-tocopherol and t-butylhydroxyanisole. A GLC study suggested that highly polyunsaturated fatty acyl constituents of the microsomal phospholipids might play an important role in epoxidation of the olefinic substrates.

Adenosine Diphosphate↗
PubMed1984

7-Glycidoxycoumarin (GOC): a fluorophotometric epoxide substrate for the assay of glutathione S-transferase activity.

7- Glycidoxycoumarin ( GOC ), a new fluorophotometric epoxide substrate for glutathione S-transferase (GSH TFase ), was conjugated regiospecifically with GSH at pH 6.5 in rat liver cytosol to yield S-(2-hydroxy-3-(7'- coumaroxy )-1-propyl)glutathione which was isolated by HPLC and identified with an authentic specimen by 13C NMR spectroscopy. The conjugation product formed in the incubation media consisting of GOC , GSH, and 9000 g supernatant fractions from various tissues of the rat, was directly determined by photometry of fluorescence emission at 388 nm at an excitation wavelength of 328 nm after removal of the unreacted substrate and its enzymic hydrolysis product, 7-(1',2'-dihydroxy-3'-propoxy)coumarin, by simple extraction with isobutyl alcohol in the presence of a saturating amount of sodium chloride. Stability of GOC at pH 6.5 markedly retarded its autoconjugation with GSH and made the fluorophotometric method sensitive enough to assay small GSH TFase activities in gel column chromatographic fractions as well as in various tissues of the animals. Apparent Km and Vmax for GOC in rat liver cytosol were 55 microM and 7.41 nmole/mg protein/min, respectively. GSH conjugation of GOC was catalyzed by at least two isozymes, E and AA, of hepatic GSH TFases .

Animals↗
PubMed1984

Studies on relationship between cysts and granulomas in murine cryptococcosis.

The histopathology of murine cryptococcosis was observed until the 55th day and particular attention was paid to whether or not cysts, which had been formed in the brain, could change to granulomas. Cryptococcus neoformans RIB-12M was used in this experiment. As experimental animals, five-week-old male BALB/c mice, weighing 20-22 g, were used. An infective inoculum was prepared by adjusting the number of cryptococci to 10(6) or 5 X 10(6)/0.2 ml. Each mouse was inoculated intravenously with 0.2 ml of the cell suspension, and the colony forming unit of the brain and liver, and the histopathological findings in various visceral organs were investigated. 40 X 10(4) colonies grew from 100 mg of the brain tissue of the eighth day. Thereafter, the number increased gradually. It reached 500 X 10(4) on the 20th day. The colony forming unit from the liver reached a peak on the 12th day (250 X 10(4] and thereafter the number decreased gradually. Histopathologically, the brain and liver were severely affected with the fungus. In the brain cysts with cryptococci continued to increase until the end of the experiment. On the other hand, in the liver several purulent foci appeared on the second day. On the eighth day numerous mononuclear cells accumulated at the foci and their lesions changed to granulomatous ones with cryptococci. The number of granulomatous lesions reached a peak on the 16th day in the mice inoculated with 5 X 10(6) cryptococci, and thereafter showed a tendency to decrease gradually.

Animals↗