Dichloromethane Potentiation of Carbon Tetrachloride Hepatotoxicity in Rats

Concomitant treatment of rats with a nonhepatotoxic dose ofdichloromethane (6 mmol/kg, ip) significantly potentiated thehepatotoxicity of carbon tetrachloride (2 mmol/kg, ip). Toxicitywas determined by increases in serum sorbitol dehydrogenaseand alanine aminotransferase activities measured 24 hr followingthe treatments. Dichloromethane did not affect the lipid peroxidationinduced by carbon tetrachloride as determined by conjugateddiene formation in hepatic microsomal lipids. The covalent bindingof [¹⁴C]Cl₄, metabolites to microsomal lipids was increasedsignificantly by dichloromethane. The results suggest that dichloromethanepotentiates carbon tetrachloride hepatotoxicity by increasingcovalent binding of its metabolites to hepatic microsomal lipids.     

Physiologically Based Pharmacokinetic Estimated Metabolic Constants and Hepatotoxicity of Carbon Tetrachloride after Methanol Pretreatment in Rats

A single 6-hr exposure to inhaled methanol (MeOH) has been shown to enhance carbon tetrachloride (CCl₄) hepatotoxicity. The objective of the present study was to use gas uptake data and the development of a physiologically based pharmacokinetic model (PBPK) to determinein vivochanges in CCl₄metabolism resulting from MeOH pretreatment. Adult male F344 rats (167–197 g) were exposed to 10,000 ppm MeOH (constant concentration) via inhalation for 6 hr. Individual rats were exposed using gas uptake techniques to CCl₄alone or to CCl₄either 24 or 48 hr after initiation of MeOH pretreatment. The following initial concentrations were used for CCl₄: 0, 25, 100, 250, and 1000 ppm with exposures lasting 6 hr.V_max(metabolic rate) was estimated from gas uptake data andK_m(Michaelis constant) was assumed constant after methanol pretreatment. For CCl₄alone,V_maxwas 0.11 mg/hr (V_maxc= 0.37 mg/hr/kg) andK_mwas 1.3 mg/liter.V_maxwas 0.48 mg/hr (V_maxc= 1.6 mg/hr/kg) for the 24-hr MeOH + CCl₄group andV_maxwas 0.18 mg/hr (V_maxc= 0.6 mg/hr/kg) for the 48-hr MeOH + CCl₄group. For CCl₄alone, serum markers of hepatotoxicity alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) were increased significantly only at 1000 ppm CCl₄. Both serum markers of hepatotoxicity in the 24-hr MeOH + CCl₄group increased as a function of CCl₄concentration when compared with 0 ppm CCl₄controls. The maximum increase occurred at 1000 ppm CCl₄, where ALT and SDH increased by 392- and 286-fold, respectively. At 100, 250, and 1000 ppm CCl₄, ALT and SDH values for the 24-hr MeOH + CCl₄groups were significantly increased relative to control (0 ppm CCl₄), CCl₄alone, and 48-hr MeOH + CCl₄. ALT and SDH levels in the 48-hr MeOH + CCl₄groups were not statistically different from the respective CCl₄alone groups.     

Immunotoxicologic Assessment of Subacute Exposure of Rats to Carbon Tetrachloride with Comparison to Hepatotoxicity and Nephrotoxicity

Immunotoxicologic Assessment of Subacute Exposure of Rats toCarbon Tetrachloride with Comparison to Hepatotoxicity and Nephrotoxicity.SMIALOWICZ, R.J., SIMMONS, J. E., LUEBKE, R. W., AND ALLIS,J. W. (1991). Fundam. Appl. Toxicol 17, 186-196. The immunotoxicity,hepatotoxicity, and nephrotoxicity of subacute exposure to carbontetrachloride (CCI4) were evaluated in young adult (8-9 weeksold) male Fischer 344 rats dosed by gavage with CCI4 for 10consecutive days at 0, 5, 10, 20 or 40 mg/kg/day. Two days followingthe last treatment rats were evaluated for alterations in immunefunction by monitoring the following; body and lymphoid organweights; mitogen and mixed leukocyte reaction lymphoproliferativeresponses; natural killer cell activity; and cytotoxic T lymphocyteresponses. A separate group of similarly dosed rats was immunizedwith sheep red blood cells (SRBQ on Day 9 of dosing, and theprimary antibody response was assessed 4 days later. Hepaticand renal toxicity were assessed 2 days after the last treatmentby monitoring organ weights, serum indicators of hepatic andrenal damage, and hepatic cytochrome P450 levels, as well asby histological evaluation. Significant increases in relativeliver weights were observed in rats dosed at 40 mg/kg/day. Histologically,these livers displayed mild to moderate vacuolar degenerationand minimal to mild hepatocellular necrosis. In addition, serumlevels of aspartate aminotransferase and alanine aminotransferasewere elevated at this dosage, as well as at 20 mg/kg/day. Therewere no renal effects observed at these dosages of CCU. In addition,no consistent alterations were observed in the immune parametersexamined in these same animals nor in the rats immunized withSRBC. Furthermore, there was no difference in the antibody responseto SRBC in another set of rats dosed at 40, 80, or 160 mg/kg/dayCCI⁴. These results indicate that CCU is not immunotoxic inthe rat at dosages that produce overt hepatotoxicity.     

Mechanism of Early Carbon Tetrachloride Toxicity in Cultured Rat Hepatocytes

Abstract: CCl₄ causes liver necrosis in a dose-dependent manner in vivo. However, we found that primary rat hepatocytes in culture were killed after a 2 hr incubation with carbon tetrachloride gas at CCl₄ partial pressures above a threshold between 45 and 54 mmHg. Below this threshold concentration no increase in hepatocyte death was observed. We sought to explain the very abrupt CCl₄ concentration threshold for hepatocyte death. Two inhibitors of cytochrome P450 2E1, cimetidine and diallyl sulfide, inhibited lipid peroxidation as measured by production of isoprostanes, but did not reduce hepatocyte death from CCl₄. At 37°, CCl₄ accelerated the mitochondrial permeability transition in vitro, at a threshold CCl₄ concentration similar to that which caused hepatocyte death. Phospholipase A₂ inhibitors, mepacrine and 4-bromophenacyl bromide, inhibited the increase in mitochondrial permeability, but did not inhibit hepatocyte death caused by CCl₄. Rat liver microsomal lipids were used to make liposomes loaded with Ponceau Red (FW 760.6). No leakage of Ponceau red was found at CCl₄ concentrations greater than the threshold for cell death. However, CCl₄ caused acceleration of liposome fusion, over the CCl₄ concentration range spanning the threshold for hepatocyte death. Early hepatocyte death in cell culture is independent of metabolism of CCl₄, and may be related to direct effects of CCl₄ on intracellular membranes.     

Hepatic Failure Leads of Lethality of Chlordecone-Amplified Hepatotoxicity of Carbon Tetrachloride

Hepatic Failure Leads to Lethality of Chlordecone-AmplifiedHepatotoxicity of Carbon Tetrachloride. SONI, M. G., AND MEHENDALE,H. M. (1993). Fundam. Appl. Toxicol. 21, 442–450. Chlordecone (Kepone) amplification of CCl₄ toxicity occurs atsmall, nontoxic levels of chlordecone and CC1₄ and results inhighly increased irreversible hepatotoxicity culminating inlethality. Although it is generally assumed that CCl₄ lethalityis due to hepatic failure, no definitive studies are availablein the literature bridging massive liver failure and death.The present studies were designed to evaluate whether hepaticfailure is the cause of the lethality during chlordecone-amplifiedCCl₄ toxicity. Male Sprague-Dawley rats were maintained on controlor a chlordecone (10 ppm) diet for 15 days and injected withCCl₄ (100 µl/kg, ip) on Day 16. Rats were killed at 0,6, 12, 24, 36, and 48 hr after CCl₄ challenge. Hepatic failurewas evaluated by measuring plasma glucose, ammonia, bilirubin,aspartate trans-aminase (AST), alanine transaminase (ALT), sorbitoldehydrogenase (SDH), hepatic ATP, glycogen, and by histologicaland histomorphometric analyses. Plasma creatinine, urea, andkidney histopathology were also assessed for possible renalinjury. As expected CCl₄ administration to chlordecone-pretreatedrats resulted in 20% lethality by 36 hr, which progressed withtime, and all rats died within 72 hr. A significant and progressivehypoglycemia was observed with a 60% reduction in plasma glucoseat 48 hr. Hepatic glycogen content dropped precipitously. Similarly,hepatic ATP levels remained suppressed (80% of control) at allthe time points studied. Plasma ammonia levels were significantlyelevated, and by 48 hr, a threefold increase was observed. PlasmaALT, AST, SDH, and bilirubin increased progressively until thedeath of rats receiving the chlordecone + CCl₄ combination.Histopathologically, the liver sections revealed a progressiveand irreversible damage evidenced by vacuolation, accumulationof fat, and increase in hepatocellular necrosis resulting indisrupted hepatolobular structure. Administration of the samedose of CCl₄ to rats maintained on a normal diet resulted inonly marginal changes in plasma enzymes, no increase in serumbilirubin, and no significant injury in liver sections at 24hr. CCl₄ administration to chlordecone-pretreated rats resultedin a marginal increase in plasma creatinine and urea only atlater time points. Histopathological examination of sectionsof kidneys from rats receiving either chlordecone + CCl₄ combinationor the same dose of CCl₄ alone did not reveal any evidence ofsignificant renal injury. The clinical end points of hepaticfunction measured in the present study are consistent with thesequel of hepatic failure and hepatic encephalopathy leadingto animal death in chlordecone-amplified CCl₄ toxicity.     

Stimulated Tissue Repair Prevents Lethality in Isopropanol-Induced Potentiation of Carbon Tetrachloride Hepatotoxicity

Published reports on the alcohol potentiation of CCl₄toxicity indicate that in spite of enhanced hepatotoxicity there is no increase in lethality. The objective of this study was to investigate the mechanism involved in animal survival despite significantly enhanced liver injury. Male Sprague–Dawley rats (175–225 g) were treated with isopropanol (ISOP, 2.5 ml/kg, 25% aqueous solution, po) 24 hr prior to CCl₄(1 ml/kg, ip) administration. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and [³H]thymidine (³H-T) incorporation into hepatonuclear DNA were measured during a time course (0–96 hr) after CCl₄administration. Liver sections were examined for histopathology and cell cycle progression by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Maximum injury was observed at 36 hr in both the groups as indicated by elevated plasma enzyme levels and by histopathology. The extent of injury in the ISOP + CCl₄group was higher than that in the H₂O + CCl₄group. Plasma enzyme activity returned to control levels by 60 hr, indicating recovery from injury in both groups. Maximum³H-T incorporation occurred at 48 hr in both groups (ISOP + CCl₄; vehicle + CCl₄), indicating maximum stimulation of S-phase synthesis. PCNA studies revealed a corresponding stimulation of cell cycle progression. The wave of S-phase synthesis and cell cycle progression returned to control levels in the H₂O + CCl₄group by 60 hr but continued up to 72 hr in the ISOP + CCl₄group. These findings support the hypothesis that in response to increased infliction of CCl₄injury by isopropanol, augmented stimulation of cell division and tissue repair restrain the progression of injury and restore hepatic structure and function, thereby allowing the rats to survive. Further, antimitotic intervention with colchicine (1 mg/kg, ip) led to decreased S-phase synthesis, followed by 60% lethality in the isopropanol-pretreated group in contrast to 40% lethality in the group receiving CCl₄alone (H₂O + CCl₄). These findings suggest that greater stimulation of tissue repair restrains the progression of ISOP-enhanced infliction of CCl₄liver injury and accounts for recovery from enhanced liver injury and animal survival. The findings are consistent with a two-stage model of toxicity wherein liver injury is linked by progression or regression of injury, which is governed by the extent of tissue repair to the final outcome.     

Pretreatment with Drinking Water Solutions Containing Trichloroethylene or Chloroform Enhances the Hepatotoxicity of Carbon Tetrachloride in Fischer 344 Rats

Pretreatment with Drinking Water Solutions Containing Trichloroethyleneor Chloroform Enhances the Hepatotoxicity of Carbon Tetrachloridein Fischer 344 Rats. Steup, D. R., Wiersma, D., McMillan, D.A., and Sipes, I. G. (1991). Fundam. Appl. Toxicol. 16, 798–809.Previous studies have demonstrated that various compounds, includingthe common groundwater contaminants trichloroethylene (TCE)and chloroform (CHCl³), can produce a synergistic toxic responsewhen coadministered with the model hepatotoxicant carbon tetrachloride(CCI₄. This phenomenon has not, however, been demonstrated followingadministration of these compounds in drinking water. Initialexperiments indicated that Fischer 344 (F-344) rats were significantlymore sensitive to these effects than the more commonly utilizedSprague–Dawley strain. To establish the suitability ofthis strain as a model, a variety of indicators of hepatotoxicitywas evaluated and compared to histological evidence of injury24 hr after dosing with CCl₄ or a combination of CCl₄ + TCE.Plasma alanine aminotransferase (ALT) activity was the mostreliable indicator of hepatic injury and was well-correlatedwith the histologic data. Dose–response studies utilizingsimultaneous ip dosing confirm the sensitivity of the F-344rat, demonstrating synergistic toxicity at doses as low as 0.165mmol/kg of CCl₄ and 0.6 mmol/kg of TCE. Synergism was also detectedfollowing simultaneous ip administration of 1 mmol/kg CCl₄ and0.5 mmol/kg of CHCl₃. To evaluate the effects of drinking waterexposure, rats were pretreated for 3 days with solutions containingTCE (0–40 mM) or CHCl₃ (0–8 mM) stabilized with1% Emulphor (EL-620P) as their only source of fluids. A single,ip dose of CCl₄ (1 mmol/kg) was then administered and 24 hrlater animals were killed for examination of liver histologyand determination of ALT activity. Although none of the pretreatmentswere detectably hepatotoxic, rats which drank 15 and 40 mm TCEor 8 mm CHCl₃ exhibited an enhanced response to CCl₄     

三氧化二砷、黄磷、四氯化碳的急性肝脏毒作用的研究

大鼠每日分别经口染毒三氧化二砷（45mg/kg)、黄磷（3mg/kg)、四氯化碳（990mg/kg)，连续4日后，均出现肝脏病理改变，黄磷及四氯化碳组大鼠的血清GPT和GOT活性明显升高，但三氧化二砷组则无显著变化，三个染毒组大鼠的血清和肝微粒体过氧化脂质含量、血清IgM和补体C3含量均较对照组显著升高。     

Hepatotoxicity and Mechanism of Action of Haloalkanes: Carbon Tetrachloride as a Toxicological Model

Abstract

Neuroexcitatory symptoms of acute poisoning of vertebrates by pyrethroids are related to the ability of these insecticides to modify electrical activity in various parts of the nervous system.

Repetitive nerve activity, particularly in the sensory nervous system, membrane depolarization, and enhanced neurotransmitter release, eventually followed by block of excitation, result from a prolongation of the sodium current during membrane excitation. This effect is caused by a stereoselective and structure-related interaction with voltage-dependent sodium channels, the primary target site of the pyrethroids.

Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed in surviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage is not observed.

Occupational exposure to pyrethroids frequently leads to paresthesia and respiratory irritation, which are probably due to repetitive firing of sensory nerve endings. Massive exposure may lead to severe human poisoning symptoms, which are generally treated well by symptomatic and supportive measures.

VI. Summary

Although pyrethroid insecticides have been introduced on a large scale fairly recently, extensive data have been published on their mode of action, and valuable information is available on potential side effects in man.

The basic mechanism of action of the pyrethroids on the vertebrate nervous system has been investigated in detail. All available evidence clearly indicates that the primary neurotoxic target site of this chemically diverse class of insecticides is confined to the voltage-dependent sodium channels in excitable membranes. The stereoselective interaction of pyrethroids with a fraction of the sodium channels results in a prolongation of the inward sodium current during excitation, as pyrethroid-modified sodium channels stay open much longer than normal. The prolonged sodium current induced by the pyrethroids results in pronounced repetitive activity, notably in sense organs, but — depending on pyrethroid structure — also in sensory nerve fibers, motor nerve terminals, and skeletal muscle fibers. Besides repetitive firing, membrane depolarization resulting in enhanced neurotransmitter release and eventually block of excitation may also occur.

Studies on sense organs in the vertebrate skin have shown that the cyano pyrethroids evoke more intense repetitive activity than the noncyano pyrethroids. This is accounted for by large, quantitative differences in the prolongation of the sodium current by cyano and noncyano pyrethroids. For a range of pyrethroids the symptoms observed in experimental animal poisoning correlate well with the extent to which the sodium current is prolonged.

Postsynaptic neurotransmitter responses are unaffected by concentrations of pyrethroids that cause marked sodium channel modification. At high concentrations insecticidal as well as noninsecticidal pyrethroid isomers cause a nonspecific suppressive effect on the postsynaptic neurotransmitter response.

Cardiovascular effects of pyrethroids can be attributed to modification of presynaptic as well as postsynaptic sodium channels.

Paresthesia and other peripheral sensory phenomena, e.g., respiratory irritation, are repeatedly experienced in man after occupational exposure to cyano pyrethroids in particular. These symptoms, which are most likely caused by repetitive firing of sensory nerve endings, should be considered a warning of overexposure, indicating that adequate preventive measures should be taken. The quality as well as the intensity of the peripheral sensory phenomena depends not only on pyrethroid structure, but also varies with the formulation and with environmental factors.

The question whether repeated occurrence of peripheral repetitive firing may eventually lead to injury of sensory nerve endings or central sensory adaptation remains unanswered. The guinea pig flank provides an adequate model to quantify the cutaneous sensations of pyrethroids. This model may be particularly useful to compare the degree of skin sensory irritation caused by different formulations of pyrethroids and could also be of value to investigate possible chronic effects.

Lethal and near-lethal doses of pyrethroids cause sparse axonal damage in a fraction of the exposed animals, which is reversed after cessation of exposure. Threshold concentrations from acute and chronic studies are available. After prolonged chronic exposure to lower doses of pyrethroids axonal damage has not been observed. It has been suggested that the histopathological changes are unrelated to the basic neuroexcitatory action of pyrethroids. The hen sciatic nerve is not suitable for studying pyrethroid-induced nerve damage, as — in contrast to organophosphates — birds are highly insensitive to pyrethroids.

The limited information available on neurobehavioral effects of pyrethroids is difficult to evaluate, as the significance of such data for toxicological risk assessment is still under debate.

Established anticonvulsants are only moderately effective in the treatment of acute pyrethroid poisoning in animals and man. The results of animal experiments indicate that mephenesin and related compounds, combined with atropine to suppress cholinergic side effects, are the more promising antidotes presently known.

Although severe acute human poisoning with pyrethroids in the Western Hemisphere seems very unlikely, recent experience in the People's Republic of China shows that these insecticides should certainly not be considered harmless. However, with adequate therapeutic treatment, the prognosis of acute pyrethroid poisoning is generally good.     

Inhalation Carcinogenicity and Chronic Toxicity of Carbon Tetrachloride in Rats and Mice

Carcinogenicity and chronic toxicity of carbon tetrachloride were examined by inhalation exposure of 50 F344 rats and 50 BDF1 mice of both sexes to carbon tetrachloride at 0 (clean air), 5, 25, or 125 ppm (v/v) for 6 h/day, 5 days/wk, for 104 wk. Incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and of adrenal pheochromocytomas in mice of both sexes were significantly increased dose-dependently. Hepatocellular carcinomas and cirrhosis significantly occurred in the 125-ppm-exposed rats of both sexes, and 3 cases of hepatocellular carcinomas and increased incidences of hepatic altered cell foci were noted in the 25-ppm-exposed female rats. Hepatocellular carcinomas were induced in mice of both sexes at 25 and 125 ppm, and hepatocellular adenomas occurred in females at 5 ppm without any degenerative or necrotic change in hepatocytes. Hepatocellular carcinomas metastasized to the lung. The chronic hepatotoxicity was characterized by cirrhosis, fibrosis, and fatty change in rats, and ceroid deposition, bile-duct proliferation, and hydropic change in mice. Survival rates were decreased in the 125-ppm-exposed rats and mice of both sexes and in the 25-ppm-exposed female mice, in association with decreased body weights. The decreased survival rates were considered to be causally related to both various tumors including hepatocellular carcinomas and severe chronic progressive nephropathy in rats and to hepatocellular carcinomas in mice. This study provided clear evidence of carcinogenicity for carbon tetrachloride in rats and mice. A cytotoxic-proliferative and genotoxic mode of action for carbon tetrachloride-induced hepatocarcinogenesis was suggested.     

黄根片对四氯化碳致大鼠慢性肝损伤的影响

目的：探讨黄根片对大鼠慢性肝损伤的防治作用.方法：50只Wistar大鼠随机分为空白对照组、模型组、阳性对照组（联苯双酯滴丸,0.2 g·kg-1）、黄根片高、低剂量（36 g·kg-1,9 g·kg-1）组.除空白对照组外,其余各组大鼠每周2次皮下注射四氯化碳复制慢性肝损伤模型,同时每天灌胃给药1次,连续12周,观察黄根片对慢性肝损伤大鼠血液生化指标以及肝组织病理变化的影响.结果：与空白对照组比较,模型组大鼠造模后12周体质量、残留肝组织百分率显著降低,肝脏系数、肝组织Hyp含量、血清ALT、AST含量显著升高,血清TP、Alb含量显著降低（P＜0.05或0.01）.与模型组比较,黄根片高、低剂量组灌胃给药12周能够显著提高大鼠血清TP含量和残留肝组织百分率（P＜0.05）.结论：黄根片对四氯化碳致大鼠慢性肝损伤模型有一定的保护作用.     

大豆磷脂对四氯化碳肝损伤大鼠的影响

目的评价益肝灵胶囊中辅料大豆磷脂的治疗作用。方法将实验动物分7组，即正常对照组，模型对照组，益肝灵片对照组，益肝灵胶囊对照组，大豆磷脂小、中、大剂量组。除正常对照组外，大豆磷脂组以大鼠腹腔注射四氯化碳复制实验性肝损伤模型后，给予大豆磷脂治疗，周期10d，并与益肝灵片及益肝灵胶囊进行对照。结果仅大剂量大豆磷脂能降低模型大鼠血清丙氧酸氨基转移酶（ALT），而对天门冬酸氧基转移酶（AST）及肝脏系数则无明显影响。而益肝灵胶囊和益肝灵片均能降低升高的ALT，AST和肝脏系数。结论益肝灵胶囊对肝脏的保护作用不是辅料卵磷脂所致，但一定剂量的卵磷脂可能对降低ALT有所帮助。     

灵五颗粒对四氯化碳诱导大鼠慢性肝损伤的影响

目的 研究灵五颗粒对四氯化碳(carbon tetrachloride,CCl4)致大鼠慢性肝损伤的防治作用,并探讨其可能的作用机制. 方法 将Wistar大鼠随机分为6组,正常组自由饮水,其余5组给予350 mg&#8226;L^-1苯巴比妥水溶液2周诱导肝药酶.实验第3周,用CCl4复制慢性肝损伤动物模型［50% CCl4橄榄油溶液,灌胃,首次剂量0.08 mL,以后按0.08 mL&#8226;(100 g)-¹,每周1次,连续5周］.自造模之日开始,灌胃给药,qd,连续5周.末次给药后禁食16 h,取大鼠血、肝脏、脾、胸腺,检测血清肝功能［丙氨酸氨基转移酶(alanine aminotransferase,ALT), 天冬氨酸氨基转移酶(aspartate aminotransferase,AST), 碱性磷酸酶(alkaline phosphatase,ALP)、清蛋白(albumin,ALB)、总蛋白(total protein,TP)］指标、肝组织中羟脯氨酸(hydroxyproline,Hyp)、丙二醛(malonaldehyde,MDA)含量和超氧化物歧化酶(superoxide dismutase,SOD)活性,另取肝脏做病理组织学检查,计算脏器指数. 结果 模型组大鼠有明显肝损伤表现,各给药组肝损伤均有不同程度的改善(P<0.01或P<0.05).病理组织学检查 结果 表明,肝脏病变程度均较模型组明显减轻. 结论 灵五颗粒对CCl4所致慢性肝损伤具有较好的防治作用,保肝降酶效果明显,其机制可能与抑制Hyp增多,降低MDA和升高SOD的抗氧化作用有关.     

齐墩果酸对四氯化碳所致大鼠肝纤维损伤的保护作用

目的：研究齐墩果酸对四氯化碳所致大鼠肝纤维损伤的保护作用.方法：取健康雄性SD大鼠,随机分成4组,A组正常对照组,B组模型对照组,C组齐墩果酸低剂量组（30 mg·kg-1OA溶液）,D组齐墩果酸高剂量组（60 mg·kg-1OA溶液）.除正常对照组灌胃给予花生油外,其余各组都灌胃给予40%四氯化碳花生油溶液,进行肝纤维化的造模.造模同时,正常对照组和模型对照组灌胃等容0.25%CMC-Na溶液,齐墩果酸组按分组灌胃齐墩果酸0.25%CMC-Na溶液.每日一次,连续5周.末次给药后禁食24 h,取大鼠血和肝脏,进行血清肝功能指标检测（ALT、AST、ALB、TP、HA、LN、C-Ⅳ、PC-Ⅲ）和组织病理学观察.结果：齐墩果酸各剂量治疗组大鼠血清中ALT和AST含量明显低于模型对照组（P＜0.01）,Alb含量则显著高于模型组（P＜0.01）,而TP值两组间差异无统计学意义（P＞0.05）;模型组大鼠肝纤维化指标HA、LN、C-Ⅳ、PC-Ⅲ水平明显高于空白组（P＜0.01）,而齐墩果酸各剂量治疗组大鼠血清中这四个参数水平则明显低于模型对照组（P＜0.01）.病理组织学检查表明,用药各组肝纤维病理变化明显减轻.结论：齐墩果酸对实验性肝纤维化大鼠肝细胞有保护作用及抗肝纤维化作用.     

Vitamin A Potentiation of Vinylidene Chloride Hepatotoxicity in Rats and Precision-Cut Rat Liver Slices

Pretreatment of large doses of vitamin A (VA) is known to potentiatethe hepatotoxicity of carbon tetrachloride. Therefore the effectsof 1-day VA pretreatment on VDC hepatotoxicity was examinedboth in vivo and in an in vitro system of precision-cut ratliver slices. Male Sprague-Dawley rats were pretreated with250,000 IU/kg VA by oral gavage. After 24 hr rats were administered50, 100, or 200 mg/kg VDC ip. Precision-cut liver slices wereprepared from VA pretreated rats 24 hr later and the liver sliceswere exposed for 2–8 hr to 0.025–1.0 µl VDCevaporated into the gas phase of the incubation vials. VA pretreatmentresulted in an enhancement of VDC toxicity, both in vivo andin vitro. There was a dose-dependent increase in plasma ALT24 hr after VDC treatment of rats and an increase in K⁺ leakagefrom liver slices after VDC exposure. Histological analysisof the liver or the liver slices revealed that VA+VDC treatmentresulted in centrilobular necrosis of the liver. When GdCl₃(10 mg/kg iv) was administered just before VA pretreatment ofrats, VDC toxicity was partially reversed as observed by a decreasein ALT in vivo and a decrease in the loss of K⁺ in vitro. Theseresults indicated that Kupffer cells, the resident macrophagesof the liver, were partially responsible for the VA-potentiatedVDC hepatotoxicity. One-day pretreatment of VA induced cytochromeP450IIE1 protein content as well as its enzymatic activity asmeasured by p-nitrophenol hydroxylation. Because VDC is bioactivatedby cytochrome P450IIE1, the increase in VDC hepatotoxicity afterVA may be due to an increased bioactivation of VDC in the liverand in precision-cut liver slices. Thus, more than one mechanismmay be involved in the VA enhancement of VDC hepatotoxicity.     

Assessment of Hepatic Indicators of Subchronic Carbon Tetrachloride Injury and Recovery in Rats

Assessment of Hepatic Indicators of Subchronic Carbon TetrachlorideInjury and Recovery in Rats. ALLIS, J. W., WARD, T. R., SEELY,J. C, and SIMMONS, J. E. (1990). Fundam Appl. Toxicol. 15, 558–570.To determine the course of hepatic recovery from subchronicoral administration of carbon tetrachloride (CCl₄), male F-344rats were gavaged with 0, 20, or 40 mg CCl₄/kg, 5 days/week,for 12 weeks. Exposure to CCl₄ caused dosage-dependent increasesin relative liver weight and the serum levels of aspartate aminotransferase,alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase,and cholesterol as well as a dosage-dependent decrease in hepaticcytochrome P450. Centrilobular hepatocellular vacuolar degeneration,necrosis, and cirrhosis occurred at both 20 and 40 mg/kg, withdosage-dependent severity. Reversibility of these reported effectsvaried with parameter. By Day 8 postexposure, necrosis had disappearedand all serum indicators and cytochrome P450 had returned tocontrol levels. By Day 15 postexposure, the severity of thevacuolar degeneration had decreased. Reversibility of cirrhosiswas dosage dependent; complete recovery occurred in the low-but not the high-dose group by Day 15. The disappearance ofthe increase in relative liver weight was also dependent ondosage; the low- but not the high-dose group had returned tothe control level by Day 22. In an attempt to measure persistenthepatic damage, liver uptake relative to the spleen was determinedfor a sulfur colloid labeled with technetium-99m and for tritiated2-deoxyglucose. Neither method consistently measured hepaticdamage in cirrhotic livers due, in part, to the high degreeof variability in the tracer uptake data.     

Prevention of Carbon Tetrachloride-Induced Hepatotoxicity by the Ethanol Extract of Capparis moonii Fruits in Rats

The effect of the ethanol extract of Capparis moonii Hook. f. Thoms. (Capparidaceae) fruits was studied in carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. The hepatotoxicity was induced in rats with the administration of 1 : 1 (v/v) mixture of CCl₄ in olive oil at the dose of 1 ml/kg subcutaneously on day 7. The ethanol extract of C. moonii (200 mg/kg) and the standard drug silymarin (25 mg/kg) were given orally from day 1 to day 9. The extract of C. moonii produced significant (p &lt; 0.001) lowering of the elevated Serum glutamic oxaloacetic transaminace (SGOT) Serum glutamicpyraric transaminase (SGPT), alkaline phosphatase (ALP), and a rise of depleted total protein when compared with the toxic control. The results were comparable with the standard drug silymarin.     

Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachloride in the Rat

Emulphor, a polyethoxylated vegetable oil, is now being usedwidely to incorporate volatile organic compounds (VOCs) andother lipophilic compounds into aqueous solutions for biochemical,pharmacokinetic, and toxicological studies. Previous work inthis laboratory demonstrated that 0.25% Emulphor did not alterthe kinetics or hepatotoxicity of low doses of CCl₄ comparedto when the halocarbon was given to rats orally in water. Thepresent study was undertaken as there was concern that higherconcentrations of Emulphor (necessary to maintain lipophilicVOCs in stable aqueous emulsions for extended periods) mightalter the VOCs' absorption, disposition, and/or toxicity. Dosagesof 10 and 180 mg CCl₄/kg bw were given, as an aqueous emulsionusing 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague–Dawleyrats. Serial microsamples of blood were collected from an indwellingcannula in unanesthetized, freely moving rats at intervals of2-60 min for up to 12 hr. The samples' CCl₄ content was measuredby headspace gas chromatography. Thereby, it was possible toobtain blood CCl₄, concentration-versus-time profiles. Animalswere euthanized 24 hr postdosing and blood was collected formeasurement of serum enzymes as indices of hepatotoxicity. Notoxicologically significant differences in pharmacokinetic parametersas a function of Emulphor concentration were found. Similarlythe hepatotoxic potency of 10 and 180 mg/kg CCl₄, as reflectedby elevation in serum enzyme activities, did not vary significantlywith the concentration of Emulphor utilized. Hence, it can beconcluded that Emulphor, in concentrations as high as 10% (equivalentto 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantlyaffect the absorption, disposition, or acute hepatotoxicityof CCl₄ in male Sprague–Dawley rats.     

雷竹笋汁对四氯化碳致大鼠急性肝损伤的防治作用

目的 :探讨雷竹笋汁对肝损伤的防治作用。方法 :分别对健康大鼠和预先用四氯化碳制作的肝损伤模型大鼠用不同剂量的雷竹笋汁 (Ⅰ组 2 0 5.70mg·kg 1,Ⅱ组 43 6.40mg·kg 1)灌胃 7d ,然后将健康大鼠亦用四氯化碳制备肝损伤模型 ,并另取健康大鼠作空白对照 ,测定各组大鼠血清丙氨酸氨基转移酶 (ALT)、天冬氨酸氨基转移酶 (AST)和超氧化物歧化酶 (SOD)活性及丙二醛 (MDA)含量。结果 :雷竹笋汁显著降低实验大鼠血清ALT和AST的活性 ,升高SOD活性及降低MDA含量 ,且呈量效关系。结论 :雷竹笋汁对四氯化碳致大鼠急性肝损伤有明显的防治作用 ,其机制可能与抗氧化反应有关     

丹芪益肝颗粒对慢性肝损伤大鼠的肝保护作用

［摘要］目的验证丹芪益肝颗粒对四氯化碳（CCl4）所致大鼠慢性肝纤维化模型的肝保护作用及抗纤维化作用。方法模型组及各给药组首次皮下注射40%CCl4 5 mL&#8226;kg-1，以后每3 d注射1次40% CCl4 3 mL&#8226;kg-1，正常对照组给予等容积橄榄油，持续9周，给药自造模之日开始。结果CCl4所致慢性肝纤维化大鼠有明显肝损伤及慢性纤维化表现，丹芪益肝颗粒3个剂量组肝功能指标均有不同程度的改善；5，10 g&#8226;kg-1组肝组织胶原蛋白含量较模型组均明显降低；2.5 g&#8226;kg-1组血清玻璃酸（HA）较模型组显著降低；病理组织学检查结果表明其肝脏病变程度均较模型组明显减轻。结论丹芪益肝颗粒对慢性肝纤维化大鼠具有肝保护作用及抗肝纤维化作用。