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G L Lage

Publications and source records attributed to G L Lage.

23 records · Page 2Linked to original sources
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Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

1-Propanol↗
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In vitro digitoxin metabolism. Rate-limiting step and alteration following spironolactone pretreatment.

The biotransformation of digitoxin was considered as a linear transformation comprised of dual deoxy sugar cleavages culminating with product conjugation to glucuronic acid. Digitoxin and two metabolites, digitoxigenin bisdigitoxoside and digitoxigenin monodigitoxoside, were each incubated for 1 hr with rat liver slices. Measurements of amounts of various metabolites allowed determination of rate constants, showing the cleavage of the terminal sugar from digitoxigenin bisdigitoxoside to be the rate-limiting step. The inductive action of spironolactone predominately affected the rate-limiting step.

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The fate of a major biliary metabolite of digitoxin in the rat intestine.

In the rat, the major water-soluble biliary metabolite of digotoxin is digitoxigenin monodigitoxoside glucuronide (mono-gluc). Despite its preponderance in the bile, only small amounts of mono-gluc are found in the feces. The compound may be absorbed from the intestine as the glucuronide conjugate, or it may be hydrolyzed to the parent compound, digitoxigenin monodigitoxoside (mono); the parent compound might then be absorbed from the intestine. The purposes of this study were to determine the ability of closed duodenal and cecal strips in vivo to absorb the conjugate and the parent compound, to hydrolyze the glucuronide, and to conjugate the parent mono. Absorption of mono was found to be more rapid than mono-gluc in both intestinal locations. Absorption of mono in the cecal strip was slower than in the duodenal strip. Considerable hydrolysis of mono-gluc occurred in the cecal strip; in the duodenal strip, the net process was conjugated of the parent mono. Thus, the disappearance of mono-gluc between its appearance in the bile and excretion in the feces is explained mainly by hydrolysis in the lower intestinal tract. Paradoxically, absorption of the hydrolysis product, mono, proceeds more slowly in the lower intestine, where it is hydrolyzed, than in the duodenum, where hydrolysis does not occur.

Animals↗
PubMedDate not supplied

Metabolism of digitoxin in the isolated perfused rat liver. Effect of spironolactone pretreatment.

Livers from either control or spironolactone-treated rats were perfused for a 90-min period with 30% rat blood and 3H-digitoxin. At several time periods throughout perfusation, bile was collected and a sample of blood was removed from the perfusate. Extractions were performed on both blood and bile to determine amount of polar and nonpolar metabolites at 60 min. Polar metabolites were cleaved with beta-glucuronidase and high-pressure liquid chromatography was used to separate the resultant nonpolar metabolites from blood and bile cleaved with beta-glucuronidase. Biliary excretion and perfusate disappearance of 3H-digitoxin were significantly increased in livers taken from spironolactone-pretreated animals. Both polar and nonpolar metabolites in bile were significantly increased in pretreated animals. The majority of polar metabolites produced by livers from both treated and nontreated animals were readily cleaved with beta-glucuronidase. Both biliary excretion and metabolic pattern, obtained from these studies in an isolated perfused rat liver, mimic those seen in the intact rat. Thus, the isolated perfused rat liver can be used as a model for in vivo studies of cardiac glycoside metabolism.

Animals↗