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Biomedical subjects

H A Sasame

Publications and source records attributed to H A Sasame.

18 recordsLinked to original sources
PubMed1979

High concentrations of glutathione in glandular stomach: possible implications for carcinogenesis.

In laboratory rodents, concentrations of reduced glutathione (GSH) are exceedingly high (up to 7 to 8 millimolar) in the glandular gastric tissue compared to concentrations in other portions of the gastrointestinal tract or to those of most other organs. Gastric GSH varies diurnally, with the highest levels occurring in the late afternoon or early evening. Starvation, treatment with diethyl maleate, or cold-restraint stress all caused marked decreases in stomach GSH, whereas treatment with cobaltous chloride caused an increase in the GSH concentrations. The physiological significance of the high gastric GSH is unknown, but because this endogenous compound may strongly modulate (decrease or increase) the macromolecular binding of certain chemicals capable of inducing stomach tumors, the possible role of glutathione in the pathogenesis of chemically induced gastric cancer should be considered.

Animals↗
PubMed1979

Acute pulmonary injury in rats by nitrofurantoin and modification by vitamin E, dietary fat, and oxygen.

The subcutaneous administration of nitrofurantoin to rats caused severe pulmonary damage, characterized by edema, congestion, and hemorrhage. The acute lethality of the drug was greater in rats fed vitamin E-deficient diets high in polyunsaturated fats as compared to rats fed the NIH open-formula diet. The survival times of vitamin E-deficient rats were increased if such animals were fed diets supplemented with vitamin E and/or diets containing saturated fat (lard) for 3 weeks before administration of nitrofurantoin. The toxicity of nitrofurantoin was enhanced in both the rats deficient in vitamin E and in those given vitamin E supplements and exposed to O2-enriched atmospheres. These results, in conjunction with previous metabolic studies in vitro showing redox cycling and O2 activation in rat lung microsomes in the presence of nitrofurantoin, illustrate certain similarities with the lung-toxic herbicide, paraquat, and raise the question of whether the 2 agents may be capable of damaging lungs by a common mechanism.

Animals↗
PubMed1978

In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes.

Rat lung and liver microsomes mediated the biotransformation of the pulmonary toxin, 4-ipomeanol, to an alkylating metabolite. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was strongly inhibited by carbon monoxide, which indicated the participation of a cytochrome P-450-dependent monooxygenase. Other studies with inhibitors including pyrazole, piperonyl butoxide, SKF-525A, and cobaltous chloride, and with the inducers phenobarbital and 3-methylcholanthrene, also were consistent with this view. The Km for the pulmonary microsomal alkylation pathway was more than 10-fold lower than for the hepatic microsomal pathway. There was no significant enzyme-mediated covalent binding of analogs of 4-ipomeanol lacking the furan moiety, suggesting that metabolic activation of the parent compound involves oxidation of the furan ring. Reduced glutathione prevented the microsomal alkylation by 4-ipomeanol, indicating the electrophilic nature of the alkylating metabolite.

Alkylation↗
PubMed1978

Paradoxical effects of cobaltous chloride and salts of other divalent metals on tissue levels of reduced glutathione and microsomal mixed-function oxidase components.

Treatment of animals with cobaltous chloride caused decreases in hepatic, pulmonary and renal cytochrome P-450, and alterations in levels of other components of microsomal mixed-function oxidases, which can alter the rate of biotransformation of certain drug substrates. The treatment also caused a striking, dose-dependent elevation in tissue levels of reduced glutathione (GSH), within 2 to 8 hours. The effect of cobalt on GSH occurred in all tested animal species and strains. Actinomycin-D partially prevented the cobalt-stimulated rise in hepatic GSH. Salts of several other divalent metals also produced sharply elevated levels of hepatic GSH, occurring concomitantly with decreased microsomal content of cytochrome P-450. These results suggest that pretreatment of animals with cobaltous chloride, or other divalent metal salts, could alter the disposition of certain toxic, alkylating drug metabolites not only by decreasing the rate of formation of the reactive metabolites, but also by increasing the amount of GSH available for the formation of their less reactive, less toxic, GSH conjugates.

Animals↗
PubMed1976

Biochemical changes after hepatic injury by allyl alcohol and N-hydroxy-2-acetylaminofluorene.

Administration of hepatotoxic doses of allyl alcohol and N-hydroxy-2-acetylaminofluorene (N-OH-AAF) TO adult male rats produced periportal necrosis and functional derangement of the hepatic endoplasmic reticulum within 24 h. The rates of N-demethylation of ethylmorphine and p-hydroxylation of aniline were decreased 6 h following allyl alcohol administration, but cytochromes P-450 and b5 were unchanged. In contrast, administration of NOH-AAF decreased cytochromes P-450 and b5 and the rate of aniline p-hydroxylation, but did not change the rate of N-demethylation of ethylmorphine or the activities of cytochrome c reductase and glucose-6-phosphatase. No decrease was observed in the activity of the cytosol enzyme, DT diaphorase, following allyl alcohol treatment. The changes by these periportal hepatotoxins were compared with those produced both by central and midzonal hepatotoxins and with changes occurring in the liver after surgical partial hepatectomy.

Acetaminophen↗
PubMed1976

Biochemical changes after hepatic injury from toxic doses of acetaminophen or furosemide.

The effects of hepatotoxic doses of acetaminophen and furosemide on the function and composition of hepatic endoplasmic reticulum were compared from 3 to 24 h after administration. Acetaminophen caused a significant decrease in microsomal protein concentration as early as 3 h after its administration, but furosemide did not affect the microsomal protein concentration until 24 h after the dose. Both acetaminophen and furosemide decreased the concentrations of cytochrome P-450 and cytochrome b5 in microsomes, and the activity of microsomal ethylmorphine N-demethylase and aniline hydroxylase. Glucose-6-phosphatase and UDP-glucuronyl transferase were not significantly affected by acetaminophen or furosemide administration, and neither diene conjugation nor hepatic triglycerides were increased. Incorporation of 3H-L-leucine into liver proteins was decreased by 50% after the administration of either acetaminophen or furosemide.

Acetaminophen↗
PubMed1976

Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite.

The possibility that furosemide-induced hepatic necrosis results from the formation of a chemically reactive hepatotoxic metabolite has been examined. Hepatotoxic doses of 3H-furosemide or 14C-furosemide were administered to normal mice and to mice pretreated with piperonyl butoxide, cobalt chloride, alpha-naphthylisothiocyanate or phenobarbital. Mice were killed at various time intervals and tissues were examined for necrosis, for free furosemide concentrations and for covalently bound metabolites of furosemide. Little furosemide was covalently bound to muscle, whereas the amount of covalently bound material in liver usually paralleled the severity of live necrosis after alteration by the pretreatments. The severity of hepatic necrosis failed to correlate with furosemide concentrations in liver or plasma. Furosemide was shown to be metabolically activated to an arylating intermediate by a cytochrome P-450 mixed function oxidase in hepatic microsomes. Additional experiments demonstrated that the furan ring of furosemide was the portion activated.

Alanine Transaminase↗