Protective Effect of Aucuba Japonica Against Carbon Tetrachloride-Induced Liver Damage in Rats

ABSTRACT

Pretreatment of rats with ethanol extract from leaves of Aucuba japonica (600 mg/kg/day, po) for two days protected against CCl₄-induced depression in plasma disappearance and biliary excretion of injected sulfobromophthalein (BSP) determined 24 hr after the CCI₄ challenge (0.5 ml/kg, ip). Percent recovery of BSP in bile in 60 min for control, CCI₄, extract + CCI₄ treated rats was 66.8 ± 1.9, 56.2 ± 1.4, and 68.9 ± 2.2, respectively. Pretreatment of the extract also protected CCl₄-induced increased serum glutamic-pyruvic transaminase activity and liver necrosis as demonstrated by histological evaluations. However, pretreatment of the extract did not modify the intensity of CCl₄-induced lipid peroxidation process or cytochrome P-450 destruction. The results suggest that ethanol extract of Aucuba japonica protects CCI₄ hepatotoxicity at a site in the chain events leading to necrosis but not the activation step of CCI₄ to-CC13 and CI free radicals.     

Amelioration of carbon tetrachloride-induced hepatic necrosis by post-toxicant treatment with cystamine

A quantitative animal model was developed to study amelioration of carbon tetrachloride-induced hepatic injury by post-toxicant administration of cystamine. Amelioration of CCl4-induced injury by post-toxicant cystamine treatment was compared to prevention of injury by cystamine pretreatment and possible mechanisms of the post-toxicant cytoprotective effect were investigated. Pretreatment of rats with cystamine dihydrochloride (300 mg/kg, p.o.) 30 min prior to CCl4 (0.25 ml/kg, i.p.) prevented CCl4-induced hepatic necrosis, plasma enzyme elevations, and hepatic calcium accumulation. When administered up to 12 h after CCl4, a single oral dose of cystamine inhibited necrosis in a dose-dependent manner, but did not reduce CCl4-induced plasma enzyme elevation or hepatic calcium accumulation. Cystamine post-treatment, therefore, does not appear to inhibit toxicant-induced influx of extracellular calcium into toxicant-damaged cells. This also suggests that the influx of extracellular calcium does not necessarily constitute an irreversible event leading to cell death. The mild hypothermia induced by post-toxicant treatment with cystamine did not delay the appearance of the lesion. Evidence for a slightly earlier regeneration of hepatic tissue was noted when cystamine was administered 12 h after CCl4. However, this effect was observed too long after exposure to the toxicant to account for the protection from necrosis observed 24 h after CCl4.     

Aloe-Emodin quinone pretreatment reduces acute liver injury induced by carbon tetrachloride

Aloe contains several active compounds including aloin, a C-glycoside that can be hydrolyzed in the gut to form aloe-emodin anthrone which, in turn, is auto-oxidized to the quinone aloe-emodin. On the basis of the claimed hepatoprotective activity of some antraquinones, we studied aloe-emodin in a rat model of carbon tetrachloride (CCl4) intoxication, since this xenobiotic induces acute liver damage by lipid peroxidation subsequent to free radical production. Twelve rats were treated with CCl4 (3 mg/kg) intraperitoneally and six were protected with two intraperitoneally injections of aloe-emodin (50 mg/kg; CCl4+aloe-emodin); six other rats were only aloe-emodin injected (aloe-emodin) and six were untreated (control). Histological examination of the livers showed less marked lesions in the CCl4+aloe-emodin rats than in those treated with CCl4 alone, and this was confirmed by the serum levels of L-aspartate-2-oxoglutate-aminotransferase (394+/-38.6 UI/l in CCl4, 280+/-24.47 UI/l in CCl4+aloe-emodin rats; P<0.05). We also quantified changes in hepatic albumin and tumour necrosis factor-alpha mRNAs. Albumin mRNA expression was significantly lower only in the liver of CCl4 rats (P<0.05 versus control) and was only slightly reduced in the CCl4+aloe-emodin rats. In contrast tumour necrosis factor-alpha mRNA was significantly higher (P<0.05) in the CCl4 than the control rats and almost equal in the CCl4+aloe-emodin, aloe-emodin and control groups. In conclusion, aloe-emodin appears to have some protective effect not only against hepatocyte death but also on the inflammatory response subsequent to lipid peroxidation.     

Carbon tetrachloride-induced nephrotoxicity and DNA damage in rats: Protective role of vanillin

In this study, the protective effects of vanillin were evaluated against carbon tetrachloride (CCl(4))-induced kidney damages in Wistar albino rats. CCl(4) (1 ml/kg, intraperitoneally [i.p.]) caused a significant induction of renal disorder, oxidative damage and DNA fragmentation as evidenced by increased plasma creatinine, urea and uric acid levels, increased lipid peroxidation (malondialdehyde [MDA]) and protein carbonyl. Furthermore, glutathione levels, catalase, superoxide dismutase, glutathione transferase and glutathione peroxidase activities were significantly decreased. A smear without ladder formation on agarose gel was also shown, indicating random DNA degradation. Pretreatment of rats with vanillin (150 mg/kg/day, i.p.), for 3 consecutive days before CCl(4) injection, protected kidney against the increase of MDA and degradation of membrane proteins compared to CCl(4)-treated rats and exhibited marked prevention against CCl(4)-induced nephropathology, oxidative stress and DNA damage. Kidney histological sections showed glomerular hypertrophy and tubular dilatation in CCl(4)-treated rats, however, in vanillin pretreated rats, these histopathological changes were less important and present a similar structure to that of control rats. These data indicated the protective role of vanillin against CCl(4)-induced nephrotoxicity and suggested its significant contribution of these beneficial effects.     

Improvement of phase I drug metabolism with Schisandra chinensis against CCl4 hepatotoxicity in a rat model

The seed extract of Schisandra chinensis was investigated in the rat for its restorative or therapeutic effect on Phase I hepatic drug metabolism following intoxication by carbon tetrachloride (CCl4). Male Sprague Dawley rats (220-250 g) were divided into two sets, one included rats with or without CCl4 intoxication, the other included CCl4 intoxicated rats with or without treatment of Schisandra extract. With the treatment regimen, rats received four oral doses of Schisandra (160 mg/kg) or the same volume of water at 8, 24, 32 and 48 h after CCl4 intoxication. A single oral dose (80 mg/kg) of antipyrine, a conventional probe for oxidative drug metabolism, was then administered. The levels of liver serum transaminases and cytochrome P450 were measured and the pharmacokinetics of antipyrine were assessed using a non-compartmental approach via WinNonlin. In comparison to the rats without CCl4 intoxication (t1/2: 2.2 +/- 0.9 h; Cl/F: 0.30 +/- 0.01 L/h/Kg; P450: 0.611 +/- 0.190 nmol/mg protein), CCl4 administration significantly decreased elimination (t1/2: 12.0 +/- 3.9 h) and oral clearance (Cl/F: 0.049 +/- 0.018 L/h/kg) of antipyrine, and markedly reduced the content of P450 (0.075 +/- 0.011 nmol/mg protein). Data obtained from intoxicated animals treated by Schisandra extract, compared to those without treatment, showed significant (p < 0.05) improvement in the t1/2 (4.45 +/- 1.7 h) and Cl/F (0.096 +/- 0.018 ml/h) estimates of antipyrine and a 2-3 fold increase in P450 level (0.190 +/- 0.072 nmol/mg protein). Findings in this study suggest that the seed extract of Schisandra appeared to be a promising agent for the improvement of Phase I oxidative metabolism in the liver damaged by CCl4.     

An evaluation of Lawsonia alba extract as hepatoprotective agent.

The hepatoprotective activity of an ethanol-water (1:1) extract of Lawsonia alba has been studied against CCl4-induced liver toxicity. The effects of the extract on hexobarbitone-induced sleep, BSP clearance, and on certain biochemical parameters indicated its protective role. There was no effect on bile flow. The extract did not show any signs of toxicity and the minimum lethal dose was greater than 2.0 g/kg p.o. in mice.     

Evidence for increased membrane permeability of plasmalemmal vesicles from livers of phenobarbital-induced CCl4-intoxicated rats

We have observed a marked increase in Ca2+ permeability of plasma membranes isolated from rats treated in vivo with CCl4 (2 ml/kg), after phenobarbital induction and overnight fast. Regulation of intracellular free Ca2+ is vital to cell viability and function, and the increased plasma membrane permeability, if representative of a change occurring in vivo, may be a critical biochemical determinant of CCl4-induced hepatic necrosis. Permeability to small cations of liver plasma membrane vesicles of control and CCl4-dosed rats was tested by two independent methods: 1) Ca2+ efflux after passive loading in 1 mM Ca2+, and 2) 86Rb+ uptake driven by valinomycin-induced K+ diffusion potential after 100 mM KCl-equilibrated vesicles were stripped of external K+ by cation exchange. Both indicated markedly increased permeability in plasma membranes after CCl4 in vivo. First order rate constants of biphasic Ca2+ efflux were 0.272 and 0.0516 min-1 for controls and 1.78 and 0.171 min-1 for vesicles from CCl4-treated animals. 86Rb+ uptake by CCl4 vesicles was 47% of control. Total calcium contents of plasma membranes (prepared in the absence of EGTA) by atomic absorption were 17.4 +/- 2.0 (control) and 10.9 +/- 1.2 (CCl4) nmol/mg of protein (means +/- SE, p less than 0.025). In correlation with altered biochemical function, we found 4-fold increases in the content of 11-, 12-, and 15-hydroxyeicosatetraenoic acids in plasma membranes of CCl4-treated rats. Although these specific oxidized fatty acids are unlikely to be ionophores, the ionophoretic properties of certain other oxygenated polyunsaturated fatty acids suggest a mechanism whereby accumulation of lipid oxidation products may be responsible for the altered membrane permeability we have observed after CCl4, and perhaps ultimately for cell death in CCl4-induced hepatic necrosis.     

Protective effect of saponins derived from the roots of Platycodon grandiflorum against carbon tetrachloride induced hepatotoxicity in mice

The purpose of this study was to investigate the protective effects of the saponins isolated from the root of Platycodi Radix (Changkil saponins: CKS) on carbon tetrachloride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CKS prior to the administration of CCl(4) significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activities and hepatic lipid peroxidation formation. In addition, CKS prevented CCl(4)-induced apoptosis and necrosis, as indicated by a liver histopathologic study and DNA laddering. To determine whether Fas/Fas ligand (FasL) pathway involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3, -8 activities were tested by western blotting and ELISA. CKS markedly decreased CCl(4)-induced Fas/FasL protein expression levels and in turn attenuated CCl(4)-induced caspase-3, -8 activities in mouse livers. Additionally, CKS protected the CCl(4)-induced depletion of hepatic glutathione levels. The effect of CKS on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CKS resulted in a significant decrease in the CYP2E1-dependent hydroxylation of aniline. In addition, CKS exhibited antioxidant effects on FeCl(2)-ascorbate induced lipid peroxidation in liver homogenates, and on superoxide radical scavenging activity. These findings suggest that the protective effects of CKS against CCl(4)-induced acute liver injury possibly involve mechanisms related to its ability to block CYP2El-mediated CCl(4) bioactivation and its free radical scavenging effects, and that is also protects against Fas/FasL pathway mediated apoptosis.     

Enhancing effect of preadministration of carbon tetrachloride on methylazoxymethanol acetate-induced intestinal carcinogenesis

This study concerns the modifying effect of carbon tetrachloride (CCl4) on methylazoxymethanol acetate (MAM)-induced intestinal carcinogenesis in ACI rats of both sexes. Forty five animals were given CCl4 (0.5 ml/kg body weight) through a stomach tube, followed by an i.p. injection with MAM (25 mg/kg body weight) 24 hours after CCl4 treatment. The paired administrations were done once a week for 4 weeks and animals were observed until sacrifice 30 weeks later. Pretreatment with CCl4 caused not only early death from chemical toxicity of MAM but also an increase in small-bowel tumors.     

Hepatoprotective and antioxidant effects of Bupleurum kaoi Liu (Chao et Chuang) extract and its fractions fractionated using supercritical CO(2) on CCl(4)-induced liver damage.

Fractionation with supercritical CO(2) is employed to divide ethanolic extract (E) of B. kaoi into four fractions (R, F1, F2 and F3). To assess the selectivity of the fractionation, extracts of the four fractions were characterized in terms of the hepatoprotective capacity and activity of antioxidant enzymes to against CCl(4)-induced damage. The in vitro study revealed that pretreatment with B. kaoi extract or its fractions, except F3, significantly protected primary hepatocytes against damage by CCl(4) (P<0.05). The R and F1 fractions had the highest saikosaponins content (175 and 200 mg/g dry weight, respectively) and most effectively protected the liver from damage by CCl(4). This study demonstrated that the oral pretreatment of B. kaoi (100 and 500 mg/kg), except F3, three days before a single dose of CCl(4) (CCl(4)/olive oil=1:1, 3 ml/kg, sc) was administered significantly lowered the serum levels of hepatic enzyme markers (AST and ALT) (P<0.05). A pathological examination showed that lesions, including ballooning degeneration, necrosis, hepatitis and portal triaditis were partially healed by treatment with B. kaoi extract and fractions. Oxidative stress induced by CCl(4) led to lipid peroxidation (MDA) and changes in the levels of the antioxidant enzymes in the liver. However, all the fractions, except F3, markedly suppressed lipid peroxidation and reversed the activities of the antioxidant enzymes to the normal levels.     

Modulation of the course of CCl4-induced liver injury by the anti-calmodulin drug thioridazine

Thioridazine (TDZ) administration to rats (50 mg/kg i.p.) 6 or 10 h after CCl4 treatment (1 ml/kg in olive oil i.p.) partially prevented necrogenic effects of this compound at 24 h but not at 72 h. TDZ did not have inhibitory effects on CCl4 activation, covalent binding (CB) of reactive metabolites to cellular constituents or CCl4-induced lipid peroxidation (LP). Moreover, TDZ had enhancing effects on both LP and CB. TDZ was able to increase protein and phospholipid synthesis and slightly but significantly enhanced protein but not phospholipid degradation in livers from control rats. TDZ administration decreased calcium liver content in CCl4-poisoned animals but did not change the intensity of CCl4-induced fatty liver. TDZ lowered body temperature in CCl4-treated animals during the 24 h observation period. These results and previous studies from our laboratory suggest calcium and calmodulin (CaM) participation in the CCl4 necrogenic effects on the liver but not in the hepatotoxin-induced fatty liver. TDZ-lowering effects on body temperature might also be a determinant in the delaying effects of this drug on the onset of CCl4-induced necrosis. Present experiments did allow discrimination between these two or other possible mechanisms for TDZ modulation effects.     

Du-Zhong (Eucommia ulmoides Oliv.) leaves inhibits CCl4-induced hepatic damage in rats.

The protective effects of water extract of Du-Zhong (Eucommia ulmoides Oliv.) leaves (WEDZ) and its active compound (protocatechuic acid; PCA) on liver damage were evaluated by carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats. Wistar rats were orally treated with WEDZ (0.1, 0.5, and 1.0 g/kg bw) or PCA (0.1 g/kg bw) with administration of CCl4 (0.5 ml/rat, 20% CCl4 in olive oil) for 28 consecutive days. It showed that CCl4-treated rats increased the relative organ weights of liver and kidney. CCl4-induced rats liver damage and significantly (p<0.05) increased the GOT, GPT, LDH and ALP levels in serum as compared with the control group. Treatment with WEDZ or PCA could decrease the GOT, GPT, LDH and ALP levels in serum when compared with CCl4-treated group. CCl4-treated rats also significantly (p<0.05) decreased the GSH content in liver and trolox equivalent antioxidant capacity (TEAC) in serum whereas increased (p<0.05) MDA content in liver as compared with the control group. Treatment with WEDZ or PCA also significantly (p<0.05) increased the GSH content and significantly (p<0.05) decreased the MDA content in liver. Administration of WEDZ or PCA could increase the activities of GPx, GRd and GST in liver. Liver histopathology showed that WEDZ or PCA reduced the incidence of liver lesions including hepatic cells cloudy swelling, lymphocytes infiltration, cytoplasmic vacuolization, hepatic necrosis and fibrous connective tissue proliferated induced by CCl4 in rats. The data suggest that oral administration with WEDZ for 28 consecutive days significantly decrease the intensity of hepatic damage induced by CCl4 in rats.     

Effects of salvianolic acid a on oxidative stress and liver injury induced by carbon tetrachloride in rats

In the present study, we investigated the hepatoprotective effects of salvianolic acid A, a novel antioxidant, against oxidative stress and acute liver injury induced by carbon tetrachloride (CCl(4)) in rats, and the mechanisms underlying its protective effects. Administration of CCl(4) to rats caused severe hepatic damage, as demonstrated by the significant increase in the levels of serum alanine aminotransferase, aspartate aminotransferase and classic histological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. Co-treatment with salvianolic acid A (20 mg/kg, intraperitoneally), a water-soluble extract from a Chinese traditional drug, Radix Salvia miltiorrhiza, significantly decreased CCl(4)-induced hepatotoxicity. Salvianolic acid A not only decreased serum alanine aminotransferase, aspartate aminotransferas levels and ameliorated histopathological manifestations in CCl(4)-treated rats, but also reduced oxidative stress, as evidenced by decreased reactive oxygen species production and malondialdehyde concentrations in the liver tissues, combined with elevated hepatic superoxide dismutase activity and gluthathione content. In addition, salvianolic acid A treatment remarkably reduced intrahepatic tumour necrosis factor-alpha concentrations and caspase-3 activities as compared with the CCl(4)-treated rats. The results suggested that treatment with salvianolic acid A provides a potent protective effect against acute hepatic damage caused by CCl(4) in rats, which may mainly be related to its antioxidative effect.     

Protective effects of acetylbergenin against carbon tetrachloride-induced hepatotoxicity in rats

The present study was undertaken to investigate whether or not the hepatoprotective activity of acetylbergenin was superior to bergenin in carbon tetrachloride (CCl4)-intoxicated rat. Acetylbergenin was synthesized by acetylating bergenin, which was isolated from Mallotus japonicus. The hepatoprotective effects of acetylbergenin were examined against CCl4-induced liver damage in rats by means of serum and liver biochemical indices. Acetylbergenin was administered orally once daily for 7 successive days, then a 0.5 ml/kg mixture of CCl4 in olive oil (1:1) was intraperitoneally injected at 12 h and 36 h after the final administration of acetylbergenin. Pretreatment with acetylbergenin reduced the elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma-glutamyltransferase in a dose dependent fashion. Acetylbergenin also prevented the elevation of hepatic malondialdehyde formation and depletion of glutathione content dose dependently in CCl4-intoxicated rats. In addition, the decreased activities of glutathione S-transferase and glutathione reductase were restored to almost normal levels. The results of this study strongly suggest that acetylbergenin has potent hepatoprotective activity against CCl4-induced hepatic damage in rats by glutathione-mediated detoxification as well as having free radical scavenging activity. In addition, acetylbergenin doses of 50 mg/kg showed almost the same levels of hepatoprotective activity as 100 mg/kg of bergenin, indicating that lipophilic acetylbergenin is more active against the antihepatotoxic effects of CCl4 than those of the much less lipophilic bergenin.     

Antidotal effects of deferrioxamine in experimental liver injury--role of lipid peroxidation

Pretreatment with deferrioxamine (DFO, 125-500 mg/kg i.p.) protected male mice against CCl4- or CBrCl3-induced hepatotoxicity which is closely related to an inhibition of iron-dependent lipid peroxidation monitored by ethane exhalation. For allyl alcohol, 1,1-dichloroethylene, dimethylnitrosamine, thioacetamide, bromobenzene and paracetamol no hepatoprotection was achieved with DFO indicating that lipid peroxidation is not involved as a primary mechanism of toxicity. In the case of bromobenzene a marked in vivo lipid peroxidation was observed, which was unaffected by DFO and appears therefore to be iron-dependent.     

Hepatoprotective and antioxidant effects of Commiphora berryi (Arn) Engl bark extract against CCl(4)-induced oxidative damage in rats.

Oxidative damage is involved in the pathogenesis of various hepatic injuries. In the present study the capacity of Commiphora berryi (Arn) Engl bark as an antioxidant to protect against CCl(4)-induced oxidative stress and hepatotoxicity in Albino Wistar rats was investigated. Intraperitoneal injection of CCl(4), administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin. Histopathological analysis of the liver of CCl(4)-induced rats revealed marked liver cell necrosis with inflammatory collections that were conformed to increase in the levels of SOD, GPx and CAT. Daily oral administration of methanolic extract of C. berryi (Arn) Engl bark at 100 and 200mg/kg doses for 15 days produced a dose-dependent reduction in the serum levels of liver enzymes. Treatment with C. berryi normalized various biochemical parameters of oxidative stress and was compared with standard Silymarin. Therefore, the results of this study show that C. berryi (Arn) Engl bark can be proposed to protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effect might be correlated with its antioxidant and free radical scavenger effects.     

Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats

The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction.     

Antihepatotoxic and Trypanocidal Effects of the Root Bark Extract of Uvaria chamae

Antihepatotoxic and trypanocidal activities of a root bark extract derived from Uvaria chamae were tested in vivo and in vitro. The plant material was defatted with n -hexane and extracted with 70% ethanol. The ethanol extract was recovered in a 6.13% w/w yield. The LD 50 of the ethanol extract in mice at 24 hr was 166 mg/kg (i.p.). Intraperitoneal injection of the ethanol extract into mice showed no significant effect on pentobarbitone-induced hypnosis. Pentobarbitone-induced sleep in CCl 4 -poisoned rats was significantly reduced (p&lt;0.005) by oral administration of the extract (60 mg/kg). The elevation of serum GOT, GPT, alkaline phosphatase and urea induced by CCl 4 intoxication in rats was also significantly reduced (p&lt;0.005) by the ethanol extract. Uvaria chamae ethanol extract showed a significant (p&lt;0.005) trypanocidal effect which was comparable to that of diminazine aceturate (r= 0.89). Reduction of existing parasitaemia in mice experimentally infected with Trypanasoma brucei brucei was dose-dependent.     

Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse.

In the mouse, retinol administration attenuates carbon tetrachloride (CCl4)-induced hepatic injury. We have investigated the role of cytochrome P4502E1 (CYP2E1) in this interaction. Male Swiss Webster mice were administered retinol (75 mg/kg/d) or vehicle for 3 days prior to CCl4 (30 microl/kg, ip). Hepatotoxicity produced by CCl4 was assessed by plasma alanine aminotransferase (ALT) activity and light microscopy (ALT activity of 1391+/-430 vs. 274+/-92 IU/L for vehicle + CCl4 and retinol + CCl4 treatments respectively, p < 0.05). Retinol's attenuation of liver injury was maintained when CCl4 was administered 48 h after the conclusion of the retinol pretreatment. Aniline hydroxylation activity, an indicator of CYP2E1 catalytic activity, determined on day 4 was 33.8% of untreated control in vehicle + CCl4 treatments while the retinol + CCl4 treatment group was 94.2% of untreated control. Additionally, CYP2E1 immunoreactive protein was 78% lower in vehicle + CCl4 vs. retinol + CCl4 treatment groups. Attenuation of potentiated hepatotoxicity was also observed when CYP2E1 was induced by acetone (ALT activity of 3119+/-1066 vs. 247+/-77 IU/L for vehicle and retinol treatments respectively, p < 0.05). In the mouse, retinol itself does not alter constitutive or inducible CYP2E1 expression. However, in combination with CCl4 retinol does reduce the amount of CCl4 bioactivated to its toxic metabolite. We conclude that retinol attenuates CCl4-induced hepatotoxicity by causing a decrease in CCl4 bioactivation but does not cause a decrease in CYP2E1 expression.     

Protective effects of Passiflora alata extract pretreatment on carbon tetrachloride induced oxidative damage in rats.

The leaf extract of Passiflora alata Dryander (P. alata) has been demonstrated to possess antioxidant activity in vitro. The aim of this study was to investigate the effects of P. alata leaf extract pretreatment on carbon tetrachloride-treated rats. Male Wistar rats were randomly allocated into four groups: group 1 (control - vehicle), group 2 and 3 (P. alata extract - 1 and 5mg/kg, respectively) and group 4 (trolox - 0.18mg/kg). Rats received daily pretreatment by oral gavage for 30 days followed by a single dose of CCl(4) (3ml/kg i.p. in vegetable oil) on the 30th day and were killed after 6h. The pretreatment with the P. alata extract provided significant protection to liver, evidenced by lower degree of necrosis, decreased lipid peroxidation (TBARS) and higher catalase and superoxide dismutase activities. Additionally, pretreated-rats with P. alata (5mg/kg) showed significantly decreased cardiac TBARS levels. Our results indicate that a low oral dose of P. alata leaf extract has both hepato and cardioprotective effects on rats treated with CCl(4).