2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadienone: a hepatic metabolite of butylated hydroxytoluene in rats.
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Biomedical subjects
Publications and source records attributed to K Hiraga.
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The effects of vitamin K on hemorrhagic death induced by dietary butylated hydroxytoluene (BHT) were studied. Male Sprague-Dawley rats were given BHT or two phenolic antioxidants (2,4,6-tri-tert-butylphenol and 2,5-di-tert-butylhydroquinone) in combination with a 24% casein basal diet. The levels of the phenols were chosen to nearly equal LD50 (40 days). Hemorrhagic death, hemorrhage and a decrease in prothrombin index caused by 1.20% BHT were prevented by simultaneously adding phylloquinone (0.68 mumole/kg/day). Phylloquinone also inhibited the effect of the related phenolic antioxidants. Ten nanomoles of phylloquinone injected into the femoral vein on day 3 of feeding 1.2% BHT increased the prothrombin concentration from 28% of normal to 100% of normal within 18 to 24 hours. Phylloquinone oxide also prevented hypoprothrombinemia due to BHT. These results suggest that BHT-induced hemorrhagic death may be caused by direct and/or indirect vitamin K deficiency, and its mechanism may be different from those of warfarin.
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The mechanism of anti-androgenic action of a steroidal compound, TSAA-291, was summarized and discussed in reference to its drug-designing and structure-activity relationship. The target of the drug-design was to obtain a substance which is inactive in androgenic activity and is capable of antagonistically competing with androgen for the receptor. With this intention, the androgen molecule was rendered with a steric hindrance influencing upon the functional 17 beta-hydroxy group. Introduction of a bulky group at the steroidal position-13 or -16 led to anti-androgenic properties. Intense steric hindrance by introducing an enormously bulky group or complete elimination of the 17 beta-hydroxy group rather decreased the anti-androgenic activity. Of these anti-androgens thus synthesized, TSAA-291 proved to be the most active in the anti-androgen assay and also antagonistic against the uptake of [3H]testosterone by the rat ventral prostate.
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The effects of polychlorinated dibenzofurans (PCDFs), trace toxic contaminants of commercial polychlorinated biphenyl preparations (PCBs), on the induction of hepatic drug-metabolizing enzymes were studied in the rat. PCDFs were about a thousand times more potent than PCBs (Kanechlor-500) as inducers of cytochrome P-450. Rats given 10 microgram/kg of PCDFs intraperitoneally for 3 days showed significantly increased hepatic cytochrome P-450 levels. At the highest dose tested, 1000 microgram/kg, a two-fold increase of cytochrome P-450 and a three-fold increase of p-nitroanisole demethylase activity were observed. PCDFs and 3-methylcholanthrene had quite similar effects on microsomal drug-metabolizing enzymes. Both drugs increased p-nitroanisole demethylase activity strikingly and aniline hydroxylase activity moderately, but produced little change in aminopyrine demethylase activity. alpha-Naphthoflavone, which is known to be a specific inhibitor of aryl hydrocarbon hydroxylase induced by polycyclic aromatic hydrocarbons, inhibited at low concentrations p-nitroanisole demethylase activity of rats previously treated with both drugs. Further, both drugs increased the 455 nm to 430 nm peak ratios of ethyl isocyanide difference spectra. Following three daily doses of PCDFs (100 microgram/kg), cytochrome P-450 level and p-nitroanisole demethylase activity remained elevated for over 15 days, with a decrease to control levels after 30 days. Such indicates the slow excretion of PCDFs.
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The fine structure of unmyelinated cutaneous nerve fibers in newborns was examined in lesions of adnexal polyp of neonatal skin. In the neonatal cutaneous nerves, unmyelinated fibers outnumbered myelinated ones. The unmyelinated fibers consisted of Schwann cells, axons and basal lamina. Their ultrastructural organization was basically similar to that in the adult skin. However, some of the unmyelinated fibers contained axonal bundles which suggested a state of cytoarchitectual immaturity or incomplete growth. Phagocytosis of melanosomes by Schwann cells was also observed.
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