The effect of a toxic dose of acetaminophen on hepatic glutathione turnover was studied in fed and fasted rats. Following the administration of 1 gm per kg of acetaminophen, the fractional rate of glutathione turnover increased from 0.19 to 0.28 hr-1 in fed rats and from 0.43 to 0.50 hr-1 in rats fasted for 48 hr. The increase in the fractional rate of turnover was proportionally much less than the decrease in hepatic glutathione concentration resulting from the toxic dose of acetaminophen. Thus, the estimated hepatic synthesis of glutathione decreased from 0.86 and 1.50 mumole per gm liver . hr to 0.59 and 0.53 mumole per gm . hr in fed and fasted rats, respectively. The excretion of acetaminophen-sulphate was significantly decreased in fasted rats. The fraction of administered acetaminophen metabolized to the mercapturic acid, however, was similar in both groups. Nevertheless, all fasted animals had massive centrilobular necrosis whereas virtually no necrosis was observed in fed animals. The administration of sulfate did not protect against liver injury in fasted rats. In view of the similar synthesis of glutathione in fed and fasted rats following a toxic dose of acetaminophen, an inability to synthesize adequate quantities of glutathione or a decreased availability of sulfate cannot account for the increased susceptibility to liver injury in the fasted state. However, a toxic dose of acetaminophen depletes the hepatic glutathione to a lower nadir before glutathione is repleted by synthesis, and a greater amount of tissue arylation occurs during this brief period of critically depleted glutathione.

Acetaminophen↗

PubMedDate not supplied

Hepatic glutathione homeostasis in the rat: efflux accounts for glutathione turnover.

Hepatic glutathione turnover and the efflux of glutathione from the liver into bile and blood were measured in male Sprague-Dawley rats in vivo. In fed rats the efflux of glutathione into blood, calculated from the hepatic arteriovenous concentration gradient and hepatic blood flow, amounted to 12.4 +/- 1.4 nmoles min X gm liver. Together with the excretion of glutathione into bile (3.4 +/- 0.4 nmoles per min X gm liver) total efflux accounted for the hepatic turnover of glutathione of 15.2 +/- 0.9 nmoles per min X gm liver. Fasting animals for 48 hr markedly increased hepatic glutathione turnover to 26.4 +/- 1.2 nmoles per min X gm liver. Increased efflux into blood rather than increased intrahepatic catabolism accounted for this increased turnover. The systemic clearance of glutathione was 3.22 +/- 0.51 ml per min X 100 gm body weight. The efflux of glutathione from liver therefore was calculated to contribute over 90% of total glutathione inflow into the circulation, as determined from the clearance and the arterial concentration of glutathione. Thus, the liver is the major source of plasma glutathione, and turnover of hepatic glutathione in the basal state is accounted for almost entirely by efflux of glutathione from the liver. During fasting, the plasma clearance of exogenous glutathione increased to 5.32 +/- 0.35 ml per min X 100 gm body weight, and the utilization of methionine for glutathione synthesis increased markedly. The increased extrahepatic catabolism during fasting results in a decrease in plasma glutathione, which in turn may account for the observed increase in sinusoidal glutathione efflux with concomitant stimulation of the rate of hepatic glutathione turnover and of synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Cimetidine inhibits the formation of the reactive, toxic metabolite of isoniazid in rats but not in man.

The hepatotoxicity of isoniazid in rats results from the metabolic activation of acetylhydrazine, a metabolite of isoniazid, by the cytochrome P450 monooxygenase system. Inhibition of the drug-metabolizing enzyme system with a compound suitable for clinical use such as cimetidine might therefore prevent liver injury in experimental animals and in patients on isoniazid without interfering with the antituberculous activity of the drug. To test this hypothesis, we studied the effect of cimetidine on acetylhydrazine-induced hepatocellular necrosis in rats and the formation of 14CO2 from [14C]acetylisoniazid, which provides an indirect assessment of the fraction of a dose of isoniazid metabolized via the toxifying pathway. Pretreatment of rats with 150 mg per kg of cimetidine significantly decreased the extent of hepatocellular necrosis produced by 100 mg per kg of acetylhydrazine and the formation of 14CO2 from [14C]acetylisoniazid. In man, however, 300 mg of cimetidine administered every 6 hr did not decrease the formation of 14CO2 from [14C] acetylisoniazid administered concomitantly with 300 mg of isoniazid; similarly, cimetidine did not affect the urinary excretion of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine. These data demonstrate that the mechanistic information obtained in animal models cannot be applied readily in clinical practice and that measurable inhibition of acetylhydrazine metabolism to prevent isoniazid liver injury does not occur after administration of therapeutic doses of cimetidine to patients.

Animals↗

PubMedDate not supplied

Computer-assisted identification and quantification of multiple sclerosis lesions in MR imaging volumes in the brain.

Magnetic resonance (MR) imaging is the principal imaging technique for the diagnosis of multiple sclerosis (MS). However, quantifying the number and extent of lesions on MR images manually is arduous. The authors have developed a computerized three-dimensional (3D) quantitative system to assist in the identification and analysis of MS lesions in proton-density (PD)- and T2-weighted volumes of the head. The system provides intuitive, interactive operations that allow flexible extraction of information from the data. Use of the system to analyze MR examinations of a phantom containing regular "lesions" showed that accurate (average error, < 0.21 cm3) and precise (10% or better for lesions > 1 cm3) measurements of objects less than 7 cm3 is possible, and that an estimate of the quantization error predicted the uncertainty in the volume. Analysis of four MR examinations of a chronic-progressive MS patient conducted over an 18-month period was performed. A two-dimensional histogram showing the frequency of voxels with particular PD- and T2-weighted intensities revealed a distinct cluster only in histograms of sections that contained lesions. Measurements and 3D volume rendering of lesions clearly showed changes in lesion shape, position, and size.

Algorithms↗