Skin-tumour promoting activity of methyl ethyl ketone peroxide—a potent lipid-peroxidizing agent

The tumour-promoting activity of methyl ethyl ketone peroxide (MEKP) was tested on the skin of hairless mice using a two-stage initiation-promotion protocol. When ultraviolet radiation in the UVB region (280–320 nm) was used as tumour initiator, MEKP showed weak promoting activity. The promotional activity of MEKP was potentiated by diethyl maleate, which is known to deplete intracellular glutathione, suggesting that lipid peroxidation may be important in the tumour promotion.     

Hepatic failure associated with imipramine therapy

Imipramine, a widely used antidepressant, has rarely been associated with hepatic abnormalities. In the majority of reported cases, hepatic effects have been transient and readily reversible on discontinuation of the drug. We cared for an 11-year-old boy with hepatic failure and massive cell necrosis which followed treatment with imipramine for enuresis. This therapy led to fulminant hepatic failure and subsequent liver transplantation.     

Spontaneous poisoning by Dodonea viscosa (Sapindaceae) in cattle

This communication reports a southern Brazilian outbreak of acute hepatic insufficiency in which 14 dairy animals died after consumption of Dodonea viscosa. The clinical course lasted a few hours and was characterized by apathy and staggering disorders. The main postmortem findings occurred in livers as enhanced lobular patterns and hepatocellular necrosis that ranged from centrilobular to massive. Similar clinical and pathological effects were experimentally induced by dosing a heifer with 30 g/kg of the plant's green leaves.     

过氧化甲乙酮烧伤对新西兰大白兔肾损伤的实验性研究

目的：观察过氧化甲乙酮( methyl ethyl ketone peroxide, MEKP)烧伤对新西兰大白兔肾功能的影响及肾组织的病理变化,探讨MEKP烧伤致肾损伤的机制。方法将30只新西兰大白兔随机分为普通火焰烧伤组( A组)、MEKP烧伤组( B组)及对照组,每组10只。分别于0、1、2、4 h采集血液,观察3组血清肌酐( Scr)、尿素( BUN)水平的变化情况及肾组织形态学变化。结果3组伤后0 h Scr和BUN比较差异无统计学意义(P>0．05)。伤后1、2、4 h A、B组Scr、BUN均高于对照组,且B组高于A组(P<0．05,P<0．01)。 B组肾组织病理表现为肾小管(尤其近端小管)上皮细胞变性坏死,肾小球结构破坏。结论 MEKP烧伤后肾损伤的机制为组织缺血缺氧及再灌注损伤等,同时MEKP吸收入血代谢产生大量自由基及有机酸,导致肾小管上皮细胞及肾小球基底细胞膜脂质过氧化,细胞代谢发生障碍,造成肾小管上皮细胞及肾小球进一步损伤。     

Narrowing of airway caused by ingestion of methyl ethyl ketone peroxide

Although ingestion of methyl ethyl ketone peroxide (MEKP) is rare, it carries a high risk of morbidity and mortality. This paper reports the first such case from Turkey in which a 70-year-old man unintentionally ingested MEKP in his kitchen. The patient was brought into the emergency department (ED) within 1 hour of ingestion, with the symptoms of sore throat, shortness of breath, nausea and vomiting. Visual examination of the oropharynx revealed minor burns and uvular edema. A laryngoscope examination performed in the ED showed superficial mucosal injury with edema of the oropharynx, uvula, posterior pharynx, epiglottis, arytenoids and vocal cords. Lateral cervical radiography revealed a narrowing of airway due to a thickened epiglottis. After the diagnostic evaluation was completed, the patient was admitted to the gastroenterology intensive care unit for monitoring of adverse reactions. During follow-up, the patient made an uneventful recovery. Ingestion of MEKP generally results from accidental ingestion from a container. Therefore, these containers should be kept in safe places. In addition, the priority following the ingestion of MEKP should be given to maintain open and adequate airway in the ED.     

Death from massive hepatic necrosis in infectious mononucleosis.

A case is reported of a 19-year-old youth who developed infectious mononucleosis and died 17 days after the onset of the illness. At autopsy massive hepatic necrosis was found, associated with enlargement of the liver.     

Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes, including furosemide and cephaloridine

Single intraperitoneal or intravenous injections of several 2-substituted furans and thiophenes, including furosemide and cephaloridine, produced renal tubular necrosis or hepatic necrosis in mice and rats. Pretreatment of animals with substances that altered drug-metabolizing enzymes usually altered the severity of the renal and hepatic necrosis produced by the furans and thiophenes and occasionally changed the target organ susceptibility to injury from one tissue to the other or the intraorgan zone of the lesion. Studies with a radiolabeled nephrotoxic and hepatotoxic furan, 2-[³H]furamide, showed direct correlations between the covalent binding of a chemically reactive metabolite of 2-furamide and the severity of renal and hepatic necrosis after pretreatment of mice with compounds that altered drug-metabolizing enzymes. A comparison of the covalent binding of the toxic metabolite of 2-furamide to tissues in vivo versus the covalent binding to hepatic and renal microsomal enzymes in vitro indicated that the renal necrosis was caused by the metabolic activation of 2-furamide in situ in the kidney. The covalent binding to renal and hepatic microsomal enzymes in vitro was dependent on NADPH, oxygen, and temperature and was inhibited by a carbon monoxide-oxygen atmosphere. Collectively, the data provide strong support for the hypothesis that the spectrum of tissue lesions produced in animals by many furans and thiophenes results from organ-specific metabolic transformation of parent drug to chemically reactive intermediates by cytochrome P-450 monooxygenases.     

Renal necrosis,glutathione depletion,and covalent binding after acetaminophen

A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [³H]acetaminophen (750–900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.     

Histological evidence for dissociation of lipid peroxidation and cell necrosis in bromotrichloromethane hepatotoxicity in the perfused rat liver

Bromotrichloromethane (CBrCl3)-induced hepatic lipid peroxidation and cell necrosis were studied histologically and biochemically, using isolated perfused livers from phenobarbital-pretreated rats. Lipid peroxidation was assessed by fuchsin staining of the liver slices and release of thiobarbituric acid reactive substances (TBARS) into the perfusate; necrosis was assessed by trypan blue uptake and lactate dehydrogenase (LDH) leakage. A good correlation was observed between the Schiff-positive reaction and TBARS release under various experimental conditions, supporting the validity of the fuchsin staining method for histological detection of lipid peroxidation. Lobular localization of lipid peroxidation and necrosis was as follows: Under high oxygen supply (95% O2-saturated buffer), infusion of CBrCl3 caused the Schiff-positive reaction in the pericentral to midzonal hepatocytes, irrespective of the direction of perfusion, but did not produce necrosis. Under low oxygen supply (20% O2) with retrograde perfusion, dissociation of lipid peroxidation and necrosis was observed, i.e., trypan blue uptake in the periportal zones and Schiff-positive staining in the pericentral hepatocytes. Thus, lipid peroxidation by itself may have a relatively minor role in the development of CBrCl3-induced acute hepatic cell death.     

Effect of gomisin A in the prevention of acute hepatic failure induction.

Nearly all rats develop massive hepatic cell necrosis and die upon intravenous administration of heat-killed Propionibacterium acnes followed by a small amount of Gram-negative lipopolysaccharide 7 days later. However, when such an experimental liver disorder is induced in rats raised for 4 or more weeks on food containing 0.06% of gomisin A extracted and purified from Schizandra chinensis, the survival rate rises, histological changes of the liver improve remarkably, and splenocyte reactivity to phytohemagglutinin and pokeweed mitogen as well as splenocyte interleukin 1 productivity are retained. These results suggested the possibility that the development of acute hepatic failure may be prevented with the oral administration of gomisin A.     

Antioxidative and hepatoprotective effects of magnolol on acetaminophen-induced liver damage in rats

Acute liver failure (ALF), an often fatal condition characterized by massive hepatocyte necrosis, is frequently caused by drug poisoning, particularly with acetaminophen (N-acetyl-p-aminophenol/APAP). Hepatocyte necrosis is consecutive to glutathione (GSH) depletion and mitochondrial damage caused by reactive oxygen species (ROS) overproduction. Magnolol, one major phenolic constituent of Magnolia officinalis, have been known to exhibit potent antioxidative activity. In this study, the anti-hepatotoxic activity of magnolol on APAP-induced toxicity in the Sprague-Dawley rat liver was examined. After evaluating the changes of several biochemical parameters in serum, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) were elevated by APAP (500 mg/kg) intraperitoneal administration (8 and 24 h) and reduced by treatment with magnolol (0.5 h after APAP administration; 0.01, 0.1, and 1 μg/kg). Histological changes around the hepatic central vein, lipid peroxidation (thiobarbituric acid-reactive substance/TBARS), and GSH depletion in liver tissue induced by APAP were also recovered by magnolol treatment. The data show that oxidative stress followed by lipid peroxidation may play a very important role in the pathogenesis of APAP-induced hepatic injury; treatment with lipid-soluble antioxidant, magnolol, exerts anti-hepatotoxic activity. Our study points out the potential interest of magnolol in the treatment of toxic ALF. Yen-Yi Ho and Ming-Tsung Lai contributed equally to this work.     

Evidence for participation of lipid peroxidation and iron in diquat-induced hepatic necrosis in vivo

The hepatic necrosis produced in Fischer-344 rats by diquat appears to be mediated by redox cycling of diquat with generation of reactive oxygen species. We have now tested the hypothesis that chelates of iron are important in the cytotoxicity of reactive oxygen species, possibly through initiating the cleavage of peroxyl bonds. Pretreatment with the iron chelator desferrioxamine, 0.24 mmol/kg intraperitoneally, attenuated the hepatic damage produced by diquat. No additional protection was provided by a second dose of desferrioxamine 2 hr after diquat or by administration of the iron chelator by a different route of administration (subcutaneously). Ferrous sulfate (0.36 mmol/kg, intraperitoneally) alone produced no hepatic injury, but when given 15 min before diquat, it potentiated hepatic injury and animal mortality. In contrast, biliary excretion of glutathione disulfide in response to administration of diquat was neither potentiated by pretreatment with FeSO4 nor diminished by pretreatment with desferrioxamine. The marked changes in hepatic injury produced by these pretreatments, without changes in glutathione disulfide production, indicate that shifts in thiol/disulfide equilibria are not likely to be initiating events in the pathogenesis of diquat-induced hepatic necrosis. Administration of a hepatotoxic dose of diquat quickly produced 5-fold stimulation of ethane and pentane expiration rates with return to control rates by 3 hr. Desferrioxamine markedly inhibited, and iron potentiated, hydrocarbon expiration in response to diquat. The parallel changes in diquat hepatic injury and ethane and pentane expiration rates in response to manipulation of iron availability suggest a possible causal role for Fenton chemistry and lipid peroxidation in diquat-generated, reactive oxygen-mediated hepatic injury in vivo.     

Effect of gomisin A in an immunologically-induced acute hepatic failure model

Guinea pigs were sensitized with trinitrophenylated liver macromolecular protein fraction (TNP-LP1) prepared by using sodium trinitrobenzenesulfonate of strong immunogenicity as the hapten and LP1 as the carrier protein. The administration of trinitrophenylated hepatocytes and lipopolysaccharide to these TNP-LP1-sensitized guinea pigs through the mesenteric vein 2 weeks later resulted in the induction of acute hepatic failure accompanied by massive hepatic cell necrosis in almost all of the guinea pigs. Using this experimental model, the effect of Gomisin A on the induction of immunological acute hepatic failure was examined. As a result, the administration of gomisin A remarkably improved the survival rate and serum transaminase levels of the immunologically-induced acute hepatic failure guinea pigs. Gomisin A also improved the histological changes of the liver in these guinea pigs. These results suggested that gomisin A is effective for the improvement of immunologically-induced acute hepatic failure in our experimental model.     

Gross and microscopic characteristics of liver lesions induced by direct injection of pentobarbital sodium into rats

The hepatotoxic effects of anesthetics brought about by their faulty intraperitoneal application was investigated. Using a syringe with a 26G needle, we injected 0.05 ml/rat of a 50 mg/ml solution of pentobarbital sodium directly into the livers of Sprague-Dawley rats. The animals were killed at 15, 30, or 45 minutes after injection. Massive hemorrhagic necrosis of the liver was seen in all animals injected, while focal necrosis accompanied by inflammatory cell infiltration was observed in the rats killed at 30 and 45 minutes after injection. The histological characteristics of these liver lesions were composed of three types, namely, massive hemorrhagic necrosis, focal cell infiltration separate from the necrosis, and focal necrosis with inflammatory cell infiltration. The infiltrates were composed of both neutrophils and lymphocytes. The characteristic liver lesions closely resembled the hepatic lesions produced by captopril (Helliwel et al., 1985), cyclopiazonic acid (Morrissey et al., 1985), as well as spontaneous liver lesions. The study of serum transaminase levels showed that the elevation of both SGPT and SGOT activities was correlated with the time after injection. Also, a significant increase in the total bilirubin level was noted in all animals treated.     

Protective effect of diphenylmethyl selenocyanate against CCl4-induced hepatic injury

Organoselenocyanates represent an important class of chemopreventive agent, which possess antioxidative, antimutagenic as well as cancer chemopreventive properties. The present study is an attempt to evaluate the protective effect of diphenylmethyl selenocyanate -- a synthetic organoselenocyanate against carbon tetrachloride (CCl(4))-induced hepatic damage in Swiss albino mice in vivo.Mice were pretreated with the Se-compound orally in a duration dependent manner (7 and 15 days) to observe its protective action against an acute toxic dose (24 h) of CCl(4) (single injection at a dose of 20 microl and 50 microl kg(-1) b.w.) that induced hepatic necrosis and caused DNA damage (strand breaks) in the hepatocytes.This study revealed that pretreatment with the Se-compound reduced the extent of massive hepatic necrosis in a duration dependent manner, but it had no modulatory effect on hepatocellular apoptosis caused by acute toxic doses of CCl(4). It was also found that the Se-compound could significantly (P < 0.01) prevent the CCl(4)-induced elevation of DNA damage in hepatocytes measured by comet assay in a duration dependent manner.So these findings will further strengthen the view that organoselenocyanate is an effective chemopreventive agent against acute hepatic damage, caused by halogenated alkanes such as CCl(4).     

慢性重型病毒性肝炎病理观察

目的 观察慢性重型病毒性肝炎病程中肝组织学的变化。方法 202例慢性重型病毒性肝炎患在不同病期进行肝穿刺作肝脏病理检查。结果 早、中期肝组织学主要表现为在慢性肝炎和小结节性肝硬变基础上出现大块或亚大块坏死;恢复期肝脏以大小结节混合型肝硬变为主,少数为重度慢性肝炎的病理表现;晚期和死亡肝组织结构严重破坏,肝细胞数量明显减少。结论 慢性重型病毒肝炎不同病期的组织学各有一定特点。病程中多次肝穿刺对该病病理诊断及预后判断有一定意义。     

Compartmental inhibition of hepatic glutathione reductase activities by 1,3-bis(2-chloroethyl)-N-nitrosourea (BCNU) in Sprague-Dawley and Fischer-344 rats

Administration of 1,3-bis(2-chloroethyl)-N-nitrosourea (BCNU) inhibits hepatic activities of glutathione reductase (GR) comparably in both adult male Fischer-344 (F344) and Sprague-Dawley (SD) rats in vivo. BCNU pretreatment greatly exacerbates the hepatic necrosis caused by diquat in F344 rats, but does not similarly potentiate liver injury in SD rats. The primary purpose of the present studies was to test the hypothesis that BCNU pretreatment would exhibit differences between the two strains in inhibition of GR activities in hepatic subcellular compartments that would correlate with the differing effects on diquat-induced hepatic necrosis. In the present studies, 16 h after administration of 80 mg/kg of BCNU, GR activities in the hepatic homogenates were 20-30% of activities in vehicle-treated controls. Neither the extents of inhibition nor the GR activities in hepatic cytosol, microsomes. mitochondria, or purified nuclei isolated by differential centrifugation were different between SD and F344 rats treated with BCNU. The results indicate that differences between SD and F344 rats in the effects of BCNU on susceptibilities to diquat-induced hepatic necrosis are not readily attributable to compartmentally selective inhibition of GR. In addition, hepatic O6-alkylguanine-DNA alkyltransferase (AGT, MGMT) levels were almost completely depleted in BCNU-treated rats of both strains, thus indicating that MGMT-dependent pathways are unlikely to be critical determinants of the effects of BCNU on this model of acute cell death mediated by reactive oxygen species in vivo.     

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.     

Acute, fatal, oral chromic acid poisoning.

CASE REPORT: We report a 35-year-old woman who developed severe acidosis, massive gastrointestinal hemorrhage, acute renal failure, and hepatic injury following ingestion of chromic acid (50 mL) and died 12 hours after ingestion. Postmortem liver biopsy revealed a fatty degeneration with chromium concentration 3.6 mumol/g. The kidney, with chromium concentration 2.6 mumol/g, had extensive necrosis and ischemic lesions. Erythrocyte chromium was 1903 mumol/L at 3 hours declining to 865 mumol/L at 11 hours.