Search PubMed⌕ Search

Biomedical subjects

C J Paul

Publications and source records attributed to C J Paul.

At least 37 records · Page 2Linked to original sources
PubMed1983

Isoniazid-induced hepatic steatosis in rabbits: an explanation for susceptibility and its antagonism by pyridoxine hydrochloride.

Steatosis was induced in rabbits by subacute administration of isoniazid (INH, 50 mg/kg po). Concomitant treatment with pyridoxine (vitamin B6, 25 mg/kg po) antagonized both development of the hepatic lesions and the elevation of plasma concentrations of lipids. Rabbit acetylating ability was sixfold that of male Wistar rats, a species susceptible to hepatic cell necrosis, whereas hepatic cytochrome P-450 and NADPH-cytochrome c reductase were significantly lower than that observed in control or phenobarbital-induced rats. Examination of the hepatic hydrolysis of the amide bonds of INH and acetylisoniazid (AcINH) indicated that the isonicotinoyl bond of AcINH was the bond most susceptible to amidase hydrolysis in both species; but rabbits possessed the greater amidase activity: 5- to 20-fold greater than control rats and 2- to 7-fold greater than the phenobarbital-induced rats. Consequently, INH-induced hepatic fatty degeneration in rabbits was attributed to increased hepatic exposure to INH-derived primary amine functional groups, and its antagonism by vitamin B6 was attributed to the deactivation of the primary amine by pyridoxal hydrazone formation.

Animals↗
PubMed1981

N-acetylcysteine-induced inhibition of gastric emptying: a mechanism affording protection to mice from the hepatotoxicity of concomitantly administered acetaminophen.

Swiss Webster male mice, 22 +/- 3 g, killed 17-18 h following the concomitant oral administration of acetaminophen (350 mg/kg) and N-acetyl-cysteine (NAC, 100-500 mg/kg, treated) had statistically significant lower plasma transaminases (GOT and GPT) than control mice (acetaminophen + water). Possible mechanisms underlying this protective effect of NAC were examined. NAC (500 mg/kg) reduced [14C]acetaminophen-derived radioactivity in the blood and tissues but increased the percentage of the dose in the gastrointestinal tract. Depletion of hepatic sulphydryl compounds below 75% of the control value was prevented by NAC treatment, whereas urinary excretion of mercapturate and sulfate, metabolites derived from sulphydryls, were proportionally increased and excretion of unchanged drug was decreased by NAC. Absorption of acetaminophen from the small intestine was prevented by NAC and this was attributed to an inhibition in gastric emptying. Since all changes observed following NAC treatment could be attributed to inhibition of gastric emptying, it was considered the major mechanism responsible for affording in mice protection from acetaminophen-induced hepatocellular damage following concomitant oral administration.

Acetaminophen↗
PubMed1981

Pathways of disposition of acetaminophen conjugates in the mouse.

After a single dose of [14C]acetaminophen (50 mg/kg) was administered orally to bile duct cannulated mice, 13.9% of the radioactivity was recovered in the bile while 41.2% was found in the urine in the first 3 h after administration. Analyses of biles revealed that the major biliary metabolite was acetaminophen glutathione (AG) conjugate which was derived from the hepatotoxic acetaminophen intermediate. Examination of urines showed that they contained mostly glucuronide and sulfate conjugates with no AG or its degradation products (cysteine and mercapturate). Analysis of urines collected from non-cannulated animals at 4 h showed that they contained glucuronide, sulfate, cysteine and mercapturate metabolites. Our results suggest that after formation in the liver, the majority of the glucuronide and sulfate conjugates were directly eliminated by the kidney. On the other hand, the pathway for the disposition of the glutathione conjugate was first into the bile, then reabsorption, and finally disposition into the urine as cysteine and mercapturate metabolites.

Acetaminophen↗
PubMed1981

Incorporation of D-(3H)glucosamine into normal and psoriatic epidermal glycoconjugates.

Samples of normal, uninvolved and involved psoriatic skin were maintained for 18 h in organ culture in the presence of D-(6-3H) glucosamine which is a precursor of cell-surface associated carbohydrates in the epidermis. The total incorporation into involved psoriatic epidermis (solubilized with 8 mol/l urea, 5% sodium dodecyl sulphate, 10 mmol 2-mercaptoethanol) was less than into normal or uninvolved epidermis. This decrease was found whether specific radioactivities were expressed in terms or area, wet weight or protein content of the epidermis. Electrophoresis revealed that the major labelled component in normal and uninvolved epidermis had a high molecular weight. The labelling of this material was significantly reduced in involved psoriatic epidermis. Using pig epidermis we have shown previously that this material represents mainly extracellular glycosaminoglycans and proteoglycans. The decrease labelling (and presumable synthesis) of these extracellular carbohydrates may be related to the failure of mechanisms controlling cell proliferation and to the altered cell interactions which are found in psoriatic epidermis. Electrophoresis also showed that a non-glycosylated protein, molecular weight approximately 50,000, which was present as a singly band in both normal and uninvolved epidermis was always present as a doublet band in the involved psoriatic epidermis.

Electrophoresis, Polyacrylamide Gel↗
PubMed1980

Effect of a concomitant single dose of ethanol on the hepatotoxicity and metabolism of acetaminophen in mice.

A concomitant single dose of ethanol (1 g/kg) protected mice from hepatic injury induced by acetaminophen (250 mg/kg) as evidenced by the lowering of plasma transaminases. Pharmacokinetic studies with [14C]acetaminophen indicated that ethanol enhanced the initial blood concentrations of radiolabel and its rate of elimination. A tissue distribution study suggested that these effects were probably due to an ethanol-induced inhibition of the biliary clearance of acetaminophen from the blood. Examination of the urinary and biliary metabolites indicated that ethanol inhibited the excretion of the degradation products derived from the glutathione-deactivated hepatotoxic acetaminophen intermediate. The decrease in acetaminophen induced hepatotoxicity was therefore attributed to an inhibitory effect of ethanol on the biotransformation of acetaminophen to the toxic intermediate.

Acetaminophen↗
PubMed1979

A semi-automated Bratton & Marshall micromethod for determining acetylator phenotype of rabbits using the Abbott Bichromatic Analyzer-100.

A micromethod for the determination of acetylator phenotype using the method of Bratton & Marshall (1939) J. Biol. Chem. 128, 537--550) was adapted to the Abbott Bichromatic Analyzer (ABA-100). Advantages of this procedure include: (a) the requirement for small blood samples (20 microliter) making it a suitable pediatric method and eliminating the need for venipunctures; (b) elimination of tedious manual reading of absorbances of samples and mathematical manipulation of data by the automated capabilities of the ABA-100; (c) an increase in the accuracy of the assay by reading samples at two wavelengths thereby correcting for differences in background.

Acetylation↗
PubMed1977

Effect of aspirin on a subtoxic dose of 14C-acetaminophen in mice.

The interaction of 14C-acetaminophen, 150 mg/kg (20 muCi/kg), and aspirin, 200 mg/kg po, was studied in male mice. The radiolabel was rapidly absorbed from the GI tract, achieving maximum blood levels 0.25 hr after oral dosing. Radioactivity in the blood equilibrated rapidly with the tissues and was concentrated in the liver and kidney. At 14 hr, most of the dose was eliminated in urine as the glucuronide, cysteine, sulfate, free drug, and mercapturate. Pretreatment with aspirin tended to reduce the rate and extent of acetaminophen absorption and altered the percentage of the dose excreted in the urine as sulfate, mercapturate, glucuronide, and cysteine. Interpretation of these data toxicologically as an indication of the potentiation of either toxicity or protection was not possible.

Acetaminophen↗
PubMed1977

Metabolic basis for the supra-additive effect of the ethanol-diazepam combination in mice.

1 The comination of ethanol and diazepam elicits additive or supra-additive pharmacological effects in animals and humans. Since the mouse appeared to be a reasonably good animal model for man, this species was examined to determine if a biochemical basis for these effects could be established.2 The effect of ethanol (3 g/kg, orally), administered 0.5 h before [(14)C]-diazepam (5 mg/kg, orally), on the pharmacokinetics of diazepam in male Swiss Webster mice was examined.3 At 4, 6, 8 and 12 h after dosing, blood levels of (14)C were higher in ethanol pretreated mice than in vehicle pretreated controls. A tissue distribution study indicated that ethanol had similar effects on levels of (14)C in most tissues at 2, 6 and 12 hours.4 Both pretreated and control mice eliminated approximately 25% of the dose of isotope in the urine and 50% in the faeces by 48 hours.5 Biliary excretion was the major route of clearance in mice in which the bile ducts had been cannulated and ethanol reduced excretion at all time periods examined up to 12 hours.6 Oxazepam (the glucuronide in bile) and desmethyl diazepam were the major metabolites identified in bile, plasma and brain. Ethanol reduced oxazepam levels but increased desmethyl diazepam levels, suggesting that 3-hydroxylation of desmethyl diazepam was inhibited by ethanol.7 The accumulation of the pharmacologically active desmethyl diazepam in the brains of ethanol pretreated mice offers an explanation for the supra-additive effect of the ethanol-diazepam combination on motor coordination.

Animals↗
PubMed1975

Effect of aspirin on fate of 14C-acetaminophen in guinea pigs.

The interaction of 14C-acetaminophen, 150 mg/kg (20 muCi/kg), and orally administered aspirin, 200 mg/kg, was studied in male guinea pigs. Aspirin-pretreated animals possessed higher 14C blood levels than controls. Paper chromatography of 0-6 hr urines demonstrated that pretreated animals excreted significantly greater amounts of mercapturate than controls; however, it was only a minor metabolite, accounting for 1-3% of the counts in the urine. The major metabolite, the glucuronide, accounted for 90% of the counts, with free acetaminophen and its sulfate responsible for the remaining counts. Tissue distribution studies indicated that blood plasma and kidneys from aspirin-pretreated animals possessed statistically higher 14C levels than did control tissues. Bile duct and ureter cannulation experiments indicated that aspirin inhibited the concentrating processes into the urine and bile.

Acetaminophen↗
PubMed1975

Effect of ethanol on diazepam distribution in rat.

The effect of an acute oral dose of ethanol (3 g/kg), administered 30 min prior to oral administration of 14C-diazepam (5 mg/kg), on the fate of radioactivity in rats was examined. Ethanol pretreated rats possessed higher tissue levels at 60, 90 and 120 min than control animals. Blood, liver, kidney and plasma tissues showed 1.5 fold differences, adipose tissue exhibited a 2.4 to 3.6-fold increase, with brain showing 3.9, 4.5 and 5.4 fold higher levels of 14C at 60, 90 and 120 min respectively. Octanol extraction of plasma and ethyl acetate extraction of brain tissues indicated ethanol pretreated animals possessed a higher percentage of extractable radioactivity than controls. Thin-layer chromatography of the extracts suggested that biotransformation of 14C-diazepam was inhibited by ethanol, causing brain levels of 14C-diazepam at 60 min to be 6.4 fold higher than that observed in controls.

Adipose Tissue↗