Acinar distribution of glutathione-dependent detoxifying enzymes. Low glutathione peroxidase activity in perivenous hepatocytes.

The acinar distribution of glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G-6-PDH) was examined by analyzing periportal (p.p.) and perivenous (p.v.) rat hepatocytes selectively isolated by the digitonin-collagenase perfusion. The cytosolic GST activity was higher in p.v. cells, but the microsomal GST and cytosolic GR were found to be evenly distributed in the acinus. In contrast, the activity of both the Se-dependent GPx and the microsomal (Se-independent) GPx, as well as G-6-PDH, was much lower in the p.v. than in the p.p. cells. The heterogeneous distribution of GST, GPx and G-6-PDH was confirmed by analyzing liver perfusion effluents collected after ante- or retrograde digitonin infusion. The relatively low activities of GPx and G-6-PDH in the p.v. cells could partly explain the susceptibility of this region to chemical injury.

Effect of ethanol on the microsomal glutathione S-transferase activity in glutathione-depleted rat liver.

Depletion of hepatic glutathione in male rats by starvation caused a significant increase in microsomal glutathione S-transferase activity, which was not affected by acute ethanol pretreatment. An additional depletion in fasted rats by diethylmaleate (0.5 g/kg) caused a further increase in the enzyme activity, but this increase was delayed in ethanol intoxicated rats. Although ethanol caused a small increase in hepatic microsomal lipid peroxidation in control animals, this effect of ethanol was not observed in diethylmaleate treated rats and thus was apparently not responsible for the delay in enzyme activation. It is suggested that the activation of microsomal glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene in glutathione-depleted rat liver may be produced by changes in thiol/disulfid ratio and/or some reactive oxygen species.

Effect of an acute dose of ethanol on lipid peroxidation and on the activity of microsomal glutathione S-transferase in rat liver.

Acute ethanol administration (1.5 g/kg) to fasted rats resulted in a small but significant increase in the content of conjugated dienes in the microsomal fraction of liver. Treatment with 4-methylpyrazole prior to ethanol ingestion was able to reduce the ethanol-induced lipid peroxide formation (measured as conjugated dienes). No depletion of glutathione occurred within the first 2 hrs following ethanol administration by which time lipid peroxide formation is well established. The ethanol-induced inhibition of N-ethylmaleimide-stimulated microsomal glutathione S-transferase activity correlates positively to the concentration of conjugated dienes in the microsomal fraction of liver.

Metabolic interaction between m-xylene and ethanol.

Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5-2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism. When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.