Mechanism of hepatotoxicity to periportal regions of the liver lobule due to allyl alcohol: role of oxygen and lipid peroxidation

The objective of this study was to evaluate the role of local oxygen tension in the zone-specific hepatotoxicity due to allyl alcohol. Infusion of allyl alcohol (350 microM) for 60 min into livers from normal fed rats perfused in the anterograde direction damaged virtually all cells in periportal areas of the liver lobule as indexed by trypan blue uptake (half-maximal uptake at 38 min). Under these conditions, oxygen uptake was inhibited only in periportal hepatocytes. Increasing the time of infusion of allyl alcohol to 90 min, however, caused dye uptake in virtually all cells across the liver lobule, with half-maximal staining in pericentral regions occurring at 70 min, indicating that hepatocytes in pericentral areas are not immune to damage by allyl alcohol. In livers from diethylmaleate-treated rats, the half-time for staining of periportal and pericentral regions was 27 and 39 min, respectively. Perfusion in the retrograde direction reverses the oxygen gradient in the liver. When allyl alcohol was infused in the retrograde direction for 60 min, cells in pericentral regions took up trypan blue whereas those in periportal areas were not damaged. Concomitantly, oxygen uptake was decreased only in pericentral regions. Infusion of allyl alcohol in oxygen-saturated perfusate in either direction caused release of lactate dehydrogenase and malondialdehyde. If oxygen tension was decreased by lowering the flow rate or perfusing with air-saturated buffer in the anterograde direction, however, malondialdehyde release and dye uptake due to allyl alcohol was reduced markedly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of age and sex on allyl alcohol hepatotoxicity in rats: role of liver alcohol and aldehyde dehydrogenase activities

Allyl alcohol-induced hepatotoxicity was more severe in old male rats than in young-adult male rats, as measured by release of hepatic enzymes from injured cells and loss of hepatic microsomal cytochrome P-450. The extent of toxicity in female rats was greater than in males and was unaffected by aging. The purpose of this study was to examine possible causes for these differences. The activity of alcohol dehydrogenase (ADH) with allyl alcohol as substrate was measured in liver cytosolic fractions of rats at ages representing young adulthood, middle age and old age. ADH activities were 1.7 +/- 0.1, 2.3 +/- 0.1 and 2.6 +/- 0.1 mumol/min/g of liver in male rats aged 4, 14 and 25 months, respectively. ADH activities in young-adult and old female rats were 3.8 +/- 0.1 and 3.7 +/- 0.1 mumol/min/g of liver. There was a good correlation (r = 0.99, P less than .001) between liver ADH activity and allyl alcohol-induced hepatotoxicity, measured as the release of sorbitol dehydrogenase into the bloodstream. Cytosolic free NAD+/NADH ratios in male rats were not significantly different among the three age groups; the ratios were lowest in young-adult female rats. Low Km aldehyde dehydrogenase activities in liver mitochondrial and cytosolic fractions were similar among the three age groups of male rats, and the activities in female rats were not substantially different. The results indicated that increased ADH activity is the principal cause of the age-associated enhancement of allyl alcohol hepatotoxicity in male rats.     

Hepatic failure toxins depress liver regenerative enzymes after periportal injury with allyl alcohol in the rat

Hepatic regenerative enzyme (thymidine kinase and ornithine decarboxylase) activities were significantly depressed by subcoma doses of the hepatic failure toxins (NH4+, octanoic acid, and dimethyl disulfide) after selective injury with allyl alcohol. The inhibitory effect of NH4+ was greater than that of dimethyl disulfide, even though the neurologic effects of dimethyl disulfide were approximately comparable with those of the NH4+. There appeared to be a delay in the full expression of the depressive effects of octanoic acid and dimethyl disulfide. The resistance to these two toxins, particularly dimethyl disulfide, may reflect the resistance to injury of the oxidative processes prominent in periportal hepatocyte mitochondria. In comparison with pericentral injury or two-lobe hepatectomy, periportal injury seemed equally susceptible to regenerative enzyme inhibition by NH4+ but less susceptible to the effect of octanoic acid and dimethyl disulfide.     

O2-dependent hepatotoxicity due to ethylhexanol in the perfused rat liver: mitochondria as a site of action

Toxicity of 2-ethylhexanol, a metabolite of diethylhexyl phthalate, was assessed in the perfused rat liver. Livers from starved rats were perfused with ethylhexanol (3 mM) dissolved in Krebs-Henseleit buffer (pH 7.4, 37 degrees C) saturated with 95% O2-5% CO2 in both the anterograde and retrograde direction. Following infusion of ethylhexanol, O2 uptake and ketone body formation were diminished by 50 and 80%, respectively, and cell damage, as assessed by the appearance of lactate dehydrogenase in the effluent perfusate, was apparent. Both inhibition of O2 uptake by ethylhexanol and the appearance of lactate dehydrogenase in the perfusate were dose-dependent. Only O2-rich upstream regions of the liver lobule were damaged as reflected by trypan blue uptake. Inhibition of O2 uptake by ethylhexanol was also reflected by a 60% decrease in the ATP/ADP ratio. Local rates of O2 uptake, measured using miniature electrodes placed on the liver surface, indicated that ethylhexanol only diminished O2 uptake in O2-rich upstream regions of the liver lobule regardless of the direction of flow. This phenomenon apparently can be explained by a direct effect of ethylhexanol on mitochondria in upstream regions since active state 3 rates of respiration were inhibited by ethylhexanol in isolated mitochondria. Ethylhexanol also caused a dose-dependent decrease in the mitochondrial membrane potential and an increase in the beta-hydroxybutyrate/acetoacetate (B/A) ratio. However, infusion of radical scavengers such as allopurinol, cianidanol and uric acid did not alter lactate dehydrogenase release due to ethylhexanol. Thus, the toxicity of ethylhexanol in the liver is dependent on local O2 tension and mitochondrial are primary targets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative hepatic response to bromobenzene and allyl alcohol in the vitamin D-replete and vitamin D-depleted rat

Vitamin D-depleted and vitamin D-replete rats were treated with allyl alcohol (AA) or bromobenzene (BB). The severity of the hepatotoxicity was evaluated by the serum concentrations of aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase, the histomorphological appearance of the lesions, and the amount of cytochrome P-450 destroyed. The activity of the monooxygenases was also evaluated. All parameters indicated that vitamin D depletion alone did not lead to any signs of liver toxicity nor did it modify the pattern of toxicity of either AA or BB. However, the intensity of the response in the periportal (AA treatment) and in the centrilobular (BB treatment) zones was modified by the depletion. Vitamin D depletion was accompanied by increased hepatic damage due to AA while BB resulted in less hepatic damage in vitamin D-depleted compared to vitamin D-replete animals. The metabolic profile of the liver mixed function oxidases indicated that its intraacinar distribution was modified by the depletion. Although the overall activity toward the substrates studied was not changed by vitamin D depletion, two out of the three enzyme activities studied suggested that vitamin D-depleted rats were poorer "centrilobular metabolizers" and better "periportal metabolizers" than vitamin D-replete rats. These observations correspond to increased periportal and decreased centrilobular toxicity in vitamin D-depleted animals. These results suggest that vitamin D depletion associated with severe hypocalcemia may be associated with an intraacinar modulation of enzyme systems as well as with an intraacinar difference in the susceptibility of the liver to certain chemicals.     

酒精所致精神障碍患者脂肪肝、胆结石、肝硬化的超声诊断

目的 利用超声征像探讨超声诊断酒精所致精神障碍伴发脂肪肝、肝硬化、胆结石等躯体疾病患者发病率与饮酒年限、饮酒量之间的关系。方法 对85例酒精所致精神障碍住院患者（研究组）和50例健康者（对照组）的腹部超声表现与饮酒年限、饮酒量进行对照分析。结果 研究组的脂肪肝、肝硬化、胆结石的发病率高于对照组（P〈0．05）。脂肪肝发病率与饮酒年限呈显著相关（P〈0．05）。结论 超声能及时发现酒精所致精神障碍伴发的躯体疾病,对指导临床早期发现和及时治疗起着重要的作用。     

Immunological studies on the mechanism of halothane-induced hepatotoxicity: immunohistochemical evidence of trifluoroacetylated hepatocytes

The fulminant hepatotoxicity caused by halothane has been thought to have an immunological basis because this toxicity occurs most often after repeated administration of halothane and because sera from patients recovering from severe halothane hepatotoxicity contain antibodies that bind to the surface membranes of hepatocytes of rabbits treated with halothane. In order to determine whether the major reactive metabolite of halothane, trifluoroacetyl halide, covalently binds to hepatocytes, we have developed specific and sensitive peroxidase enzyme-linked immunosorbent assays and an indirect immunofluorescence staining method for identifying trifluoroacetylated (TFA)-hepatocytes. Liver sections prepared from rats at 4 hr after halothane administration were stained preferentially in the centrilobular region with anti-TFA serum whereas livers of control rats showed no staining. The specificity of the assay for the TFA group was confirmed by the complete inhibition of the staining with 200 microM N-epsilon-TFA-L-lysine in the diluted antiserum. On the other hand, 2 mM halothane or L-lysine did not inhibit this staining. Moreover, treatment of rats with deuterated halothane resulted in significantly less staining than did halothane. At 24 hr after halothane administration, hepatocytes isolated and stained by indirect immunofluorescence showed a linear and granular pattern on their surface membranes. These results indicate that trifluoroacetyl halide either reacts directly with constituents of the plasma membranes or with other cellular components which become incorporated into the plasma membranes.     

酒精所致精神障碍住院患者家庭负担及经济费用状况调查

目的 了解酒精所致精神障碍住院患者的家庭负担及经济费用状况.方法 对216例酒精所致精神障碍住院患者应用一般情况调查表统计一般资料,家庭负担量表评定家庭负担状况,参照Cart等设计的有关精神疾病经济负担构成统计直接费用和间接费用,对上述统计结果进行对比分析.结果 入组患者家庭负担量表总分、家庭经济负担、家庭关系、家庭成员心理健康、家庭日常活动、家庭娱乐活动阳性回答率分别为72.2%、67.6%、81.9%、85.2%、58.3%、59.3%.患者因住院等原因每年贻误工作时间为125.09 d,照料者因照顾患者每年贻误工作时间为50.02 d.患者年人均总费用高达16.303元,其中个体、干部、工人、农民、无业者分别为21.480元、19.527元、17.458元、13.973元、11.780元.个体、干部患者总费用均显著高于农民和无业者(P＜0.05),其中个体患者直接费用显著高于无业者(P＜0.05),个体、干部及工人患者间接费用均显著高于农民和无业者(P＜0.05 或0.01).结论酒精所致精神障碍患者给家庭带来了沉重的负担,严重影响着患者及家庭成员的心身健康与生活质量.     

Metadoxyl in combined treatment of alcohol damage to the liver

20 patients of the study group and 12 control patients with alcoholic liver lesion received i.v. glucose and vitamins solution, lipotropic drugs. In addition, patients of the study group were given metadoxyl tablets (Baldacchi, Italy) in a dose 1500-2000 mg/day per os for 30 days. Before and after the treatment the patients underwent clinical examination, biochemical tests, ultrasonography, scintigraphy. It was found that metadoxyl stimulates normalization of liver function, is well tolerated, produced no side effects, holds perspectives for prevention and delay of hepatic cirrhosis.     

Influence of hypoxia on mitochondrial function and energy status in CCl4-induced cirrhotic rat liver

The influence of hypoxia on hepatic mitochondrial function and energy status was studied in normal and carbon tetrachloride (CCl4)-induced cirrhotic rats. Under hypoxemia of 50 mm Hg-PaO2, hepatic energy status was suppressed both in normal and cirrhotic rats. After the reversal of hypoxia, it was completely restored in normal rats concomitant with a rapid elevation of hepatic mitochondrial redox state (overshoot phenomenon) and increase in the mitochondrial oxidative phosphorylative activity. By contrast, in cirrhotic rats, such an enhancement of mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondria have little capacity to respond to the hypoxic stress. A lower resistance to hypoxic episode in cirrhotics might be attributable to the absence of mitochondrial enhancement which is a compensatory mechanism for the deranged energy metabolism of the liver.     

Effect of carvacrol on hepatic marker enzymes and antioxidant status in d-galactosamine-induced hepatotoxicity in rats

Carvacrol (2-methyl-5-(1-methylethyl)-phenol) is a predominant monoterpenic phenol which occurs in many essential oils of the family Labiatae including Origanum, Satureja, Thymbra, Thymus , and Corydothymus species. This study was designed to investigate the hepatoprotective and antioxidant properties of carvacrol on d -galactosamine (D-GalN)-induced hepatotoxicity and oxidative damage in male albino Wistar rats. D-GalN hepatotoxic rats exhibited elevation in the activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and lipidperoxidative markers such as thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides. Activities of enzymatic antioxidants (superoxide dismutase, catalase, and glutathione peroxidase) and the levels of non-enzymatic antioxidants (vitamin C, vitamin E, and reduced glutathione) in the plasma, erythrocytes, liver, and kidney decreased in the hepatotoxic rats. Oral administration of carvacrol for 21 days brought these parameters towards normal. The biochemical observations were supported by histological studies of rat liver and kidney tissues. These results suggest that carvacrol could afford a significant hepatoprotective and antioxidant effect against D-GalN-induced rats.     

阿立哌唑治疗酒精所致精神障碍对照研究

目的探讨阿立哌唑治疗酒精所致精神障碍的临床疗效及安全性。方法将64例酒精所致精神障碍患者随机分为两组各32例,分别给予阿立哌唑和奋乃静治疗,疗程6w。于治疗前及治疗6w末采用阳性症状和阴性症状量表,副反应量表评定临床疗效和不良反应。结果治疗6w末,阿立哌唑组显效率为68.8%,有效率为87.5%;奋乃静组分别为62.5%,81.3%。阳性症状和阴性症状量表评分两组总分和各因子分治疗6w末均较治疗前有极显著降低(P均<0.01),但阿立哌唑组阴性症状分较奋乃静组下降更显著(P<0.05);阿立哌唑组的肌张力增高、震颤、静坐不能和体质量增加等不良反应发生率显著低于奋乃静组(P<0.05或0.01)。结论阿立哌唑治疗酒精所致精神障碍疗效显著,安全性高,依从性好。