Glutathione S-transferases and chloroform toxicity in streptozotocin-induced diabetic rats

The glutathione S-transferase activity in liver and kidney cytosol was significantly decreased in short term diabetes induced with streptozotocin, whereas no decrease in the transferase was observed in phenobarbital-treated diabetic rats. Toxicity of chloroform was potentiated in streptozotocin- or phenobarbital-treated rats. The decrease in liver cytosolic and microsomal glutathione S-transferase activity was observed in long term diabetic rats, and only microsomal transferase activity was restored by insulin treatment. There was no release of glutathione S-transferases into the serum in the diabetic rats, and the transferases were not inhibited by streptozotocin in vitro. These results showed that glutathione S-transferase activity decreased during diabetes, and this decrease may contribute to altering drug metabolism and toxicity in diabetes.     

Effect of dietary trans-stilbene oxide on hepatic and renal drug-metabolizing enzyme activities and bromobenzene-induced toxicity in male Sprague-Dawley rats

The effect of dietary trans-stilbene oxide (TSO) on hepatic and renal xenobiotic metabolizing-enzyme activities and bromobenzene-induced toxicity was quantified in adult male Sprague-Dawley rats. Rats were fed a regular diet or the same diet supplemented with 2.5 g TSO/kg diet for 10 days. TSO treatment did not alter hepatic or renal arylhydrocarbon hydroxylase activity, but significantly increased glutathione S-transferase and uridine diphosphoglucuronyl transferase activities in both organs. In addition, TSO increased hepatic, but not renal, epoxide hydrolase activity. The same treatment did not produce adverse effects on renal or hepatic functions, but markedly potentiated bromobenzene hepatotoxicity. A single dose of bromobenzene (0.2 ml/kg) caused a slight increase in serum glutamic pyruvic transaminase (SGPT) activity and minor hepatic necrosis in animals fed the control diet; the same dose of bromobenzene markedly increased SGPT activity and produced severe hepatic necrosis in the TSO-fed animals.     

Chloroform-induced alteration of glutathione S-transferase activity

The effect of chloroform treatment on the hepatic glutathione S-transferases was studied in phenobarbital-treated rats. The apparent isozymic composition of glutathione S-transferases in hepatic cytosol was changed after chloroform treatment. Glutathione S-transferases AA, A, B, C, and D + E were observed in hepatic cytosol from untreated rats; in contrast, the catalytic activity associated with basic glutathione S-transferases, such as AA, A, B, and C, decreased with time after chloroform treatment. Glutathione S-transferase B was not detectable 2 hr after chloroform treatment, and glutathione S-transferases AA and C were scarcely detectable after 5 hr. Twenty-four hours after chloroform treatment, glutathione S-transferases A and C were clearly detectable as was D + E and a small amount of B. Hepatic cytosolic glutathione S-transferase activity was decreased by chloroform treatment, and reached a minimum at 5 hr after treatment. Corresponding to the decrease of hepatic cytosol glutathione S-transferase activity, serum glutathione S-transferase activity was elevated maximally 5 hr after chloroform treatment and returned to almost normal by 24 hr. Treatment of rats with SKF 525-A or cysteine inhibited the chloroform-induced elevation of serum glutathione S-transferase activity. The chromatographic properties of the glutathione S-transferases present in serum were similar to glutathione S-transferase D + E. Furthermore, after incubation of partially purified cytosolic glutathione S-transferases with chloroform in the presence of hepatic microsomes and NADPH, only transferase D + E was detected. The addition of bilirubin to partially purified cytosolic glutathione S-transferase decreased the basic character of glutathione S-transferases B and C. In conclusion, chloroform caused a release of hepatic cytosolic glutathione S-transferases into serum. Both the active metabolite of chloroform, which was produced by the microsomal cytochrome P-450 system, and bilirubin, which was increased by chloroform treatment, played roles in altering the properties of the glutathione S-transferases.     

Effects of glycerol-induced acute renal failure on tissue glutathione and glutathione-dependent enzymes in the rat

The activities of tissue glutathione (reduced and oxidized) and glutathione-dependent enzymes such as glutathione S-transferase (GSH S-transferase), glutathione reductase (GSSG reductase) and glutathione peroxidase (GSH-Px) were determined for control and uremic rats. Acute renal failure (ARF) was produced by glycerol-water injection. Cytosolic and microsomal GSH S-transferase activity in the kidney was decreased by 38% and 15%, respectively. Hepatic microsomal GSH S-transferase was also decreased by 40% in uremic rats. GSH-Px activity was decreased by 51% in the cytosolic fraction and 33% in the microsomal fraction in the kidney, but was not affected in the liver and whole blood. GSSG reductase activity was also decreased by 48% in the cytosolic fraction in the kidney of uremic rats. In whole blood, however, GSSG reductase activity was increased by 12-fold (0.66 +/- 0.12 mumol NADPH oxidized/min/ml blood in the control; 8.03 +/- 3.29 mumol NADPH oxidized/min/ml blood in uremia). Although the total glutathione concentrations were not significantly affected, the GSSG/GSH ratio, which is an indication of oxidative stress, was significantly increased in the liver and whole blood of uremic rats. In addition to the decreases in hepatic and renal GSH S-transferase activities, which is important in drug disposition, ARF caused decreases in GSSG reductase and GSH-Px activity, which are essential for the protection against lipid peroxidation.     

Changes in glutathione and glutathione metabolizing enzymes in erythrocytes and lymphocytes of mice as a function of age

Changes in reduced glutathione levels in liver, lung and whole blood of female Swiss-Webster mice with age were determined. In addition, glutathione content, and glutathione S-transferase and glutathione reductase activities of erythrocytes and lymphocytes of mice as a function of age were examined. Reduced glutathione content increased in liver, lung, whole blood, erythrocytes and lymphocytes with age from 3 to 9 months, reached a maximum level at 9 months of age and decreased thereafter with advanced age in all tissues. Glutathione S-transferase and glutathione reductase activities in erythrocytes and lymphocytes increased with age from 3 to 9 months, reached maximum activities at 9 months and decreased thereafter with advanced age. The glutathione content of erythrocytes from animals 18 months of age decreased by 56% as compared to 9 month old mice, while the activities of glutathione S-transferase and glutathione reductase decreased by 56 and 48%, respectively, over the same age span.     

Cofactor metals and antioxidant enzymes in cisplatin-treated rats: effect of antioxidant intervention

We explored the association between the activities of antioxidant enzymes and their metallic cofactors in rats treated with cisplatin. The antioxidant effects of aminoguanidine, and a combination of vitamins E and C were investigated. Plasma platin was significantly lower than liver and kidney. Cisplatin treatment caused significant increase in plasma Se-glutathione peroxidase activity. Activities of Se-glutathione peroxidase, glutathione S-transferase, catalase and Cu,Zn-superoxide dismutase have been found to be significantly decreased in liver and kidney compared to controls. Zn levels in these organs were diminished upon cisplatin treatment, while levels of Cu were unaffected. Interestingly, levels of iron, the cofactor of catalase, were found to be significantly increased in liver and kidney. Intervention with aminoguanidine or vitamins was generally prevented cisplatin-caused changes in the activity of enzymes and in the tissue levels of cofactor metals. These observations suggest that relation between activities of enzymes and levels of cofactor metals is multifactorial.     

Hepatoprotection of D-galactosamine-induced toxicity in mice by purified fractions from Garcinia kola seeds

The hepatoprotective effect of a biflavonoid complex, kolaviron, and its fractions from Garcinia kola seeds, together with the possible mechanisms involved was investigated in mice intoxicated with a single dose of D-galactosamine (GalNH(2)). Likewise, the ability of vitamin E to attenuate the toxicity was examined. Kolaviron, was separated by thin-layer chromatographic technique into three fractions; Fraction I, Fraction II and Fraction III with RF values of 0.48, 0.71 and 0.76, respectively. Pretreatment with kolaviron, fraction I and fraction II at a dose of 100 mg/kg for seven consecutive days before challenge with a single dose of GalNH(2) (800 mg/ kg) significantly (P<0.05) decreased serum alanine (ALT) and aspartate (AST) aminotransferases by 67%, 70%, 71% and 39%, 35%, 46%, respectively over GalNH(2)-only intoxicated mice. Vitamin E elicited respectively 65% and 39% reduction in the GalNH(2)-induced increase in the activities of these enzymes. In addition, pretreatment with kolaviron and fraction II significantly (P<0.05) decreased the activity of microsomal gamma-glutamyl transferase (gamma-GT) by 42% and 46%, respectively. Administration of kolaviron to GalNH(2)-intoxicated mice also restored glucose-6-phosphatase to level that was comparable to the control (P<0.05). These extracts except fraction III prevented the accumulation of serum and microsomal lipid peroxidation products, and also prevented the depletion of reduced glutathione (GSH) levels in the liver of GalNH(2)-intoxicated mice. Kolaviron, fraction I and fraction II at a dose of 100 mg/kg caused an induction of glutathione-S-transferase (GSH transferase) and uridyl glucuronosyl transferase (UDPGT) activities by 31%, 34%, 35% and 29%, 65%, 56%, respectively. GalNH(2)-induced toxicity was essentially prevented as indicated by a liver histopathologic study of liver slices from mice pretreated with kolaviron, fraction I and fraction II. This study shows that treatment with kolaviron, fraction I and fraction II (purified fractions from Garcinia kola) appeared to enhance the recovery from GalNH(2)-induced hepatotoxicity, and that the fractions I and II may therefore be responsible for the observed antihepatotoxic effect of kolaviron. This protection may be due to the ability of these extracts to induce the expression of phase II drug metabolizing enzymes.     

Liver Enzyme Activities after Multiple Administration of Nifedipine in Mice

Abstract: The effect of multiple nifedipine administration on hexobarbital sleeping time, liver monooxygenase and synthetase activities, lipid peroxidation and microsomal membrane fluidity were studied in male albino mice. The drug was administered orally at a dose of 25 mg/kg daily for 14 and 21 days. Nifedipine caused enzyme induction, demonstrated by shortened hexobarbital sleeping time, enhanced ethylmorphine N-demethylase, aniline 4-hydroxylase, ethoxycoumarine O-deethylase, UDP-glucuronyl transferase, glutathione S-transferase and NADPH-cytochrome c reductase activities and increased content of cytochrome P450 and cytochrome b₅. This effect persisted until the 7th day after the last dose of nifedipine. There were no changes in lipid peroxidation and fluidity of the microsomal membranes after 14-day nifedipine administration. The increased cytochrome P450 content and drug metabolizing enzyme activities could be not associated with changes in these liver microsomal membrane properties.     

Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats

Aim of the present study was planned to determine the protective role of naringin in attenuating the toxicity induced by nickel sulfate in rat liver. In this investigation nickel sulfate (20 mg/kg body weight) was administered intraperitoneally for 20 days to induce toxicity. Naringin was administered orally (20, 40 and 80 mg/kg body weight) for 20 days with intraperitoneal administration of nickel sulfate. Liver injury was measured by the increased activities of serum hepatic enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase and total bilirubin along with increased elevation of lipid peroxidation markers, thiobarbituric reactive acid substances, lipid hydroperoxides, protein carbonyl content and conjugated dienes. The toxic effect of nickel was also indicated by significantly decreased activities of enzymatic antioxidants like superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase and non-enzymatic antioxidants like reduced glutathione, total sulfhydryl groups, vitamin C and vitamin E levels were significantly decreased. Naringin administered at a dose of 80 mg/kg body weight significantly reversed the activities of hepatic marker enzymes, decreasing lipid peroxidative markers, increasing the antioxidant cascade and decreasing the nickel concentration in the liver. The effect at a dose of 80 mg/kg body weight was more pronounced than that of other two doses (20 and 40 mg/kg body weight). All these changes were supported by histopathological observations. These results clearly demonstrate that naringin has the potential in alleviating the toxic effects of nickel in rat liver.     

Effects of tebuconazole on cytochrome P450 enzymes,oxidative stress,and endocrine disruption in male rats

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450‐dependent monooxygenases, oxidative stress, and endocrine‐disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose‐dependently increased microsomal contents of cytochrome P450 and cytochrome b₅ and the activities of NADPH‐cytochrome P450 reductase, 7‐ethoxyresorufin O‐deethylase, methoxyresorufin O‐demethylase, pentoxyresorufin O‐dealkylase, 7‐ethoxycoumarin O‐deethylase, aniline hydroxylase, and erythromycin N‐demethylase. In kidney, tebuconazole increased 7‐ethoxycoumarin O‐deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7‐ethoxyresorufin O‐deethylase, methoxyresorufin O‐demethylase, 7‐ethoxycoumarin O‐deethylase, aniline hydroxylase, and erythromycin N‐demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole‐treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7‐ethoxycoumarin O‐deethylase activity in vitro (IC₅₀ = 1.50–1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S‐transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S‐transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S‐transferase activities; and produces anti‐androgenic effects in male rats.     

Hepatic mitochondrial prooxidant and antioxidant status in ethanol-induced liver injury in rats

In this study, prooxidant and antioxidant status in liver homogenates and their mitochondrial fractions were investigated in both chronic and chronic plus acute ethanol-treated rats. Increases in serum transaminase activities, as well as increases in total lipid, triglyceride, malondialdehyde (MDA) and diene conjugate (DC) levels and decreases in glutathione (GSH), vitamin E and vitamin C levels, have been observed in liver homogenates following chronic ethanol treatment (20% ethanol, v/v as drinking water for 3 months), but CuZn-superoxide dismutase (CuZnSOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities remained unchanged in postmitochondrial fractions. When an acute dose of ethanol (5 g/kg, i.p.) was given rats which had received ethanol chronically, serum transaminase activities and hepatic lipid and MDA and DC levels increased further, but GSH levels and antioxidant enzymes decreased more compared to the chronic ethanol-treated rats. There were no significant differences in the levels of MDA, DC and protein carbonyl and the activities of GSH-Px and GST in the hepatic mitochondrial fraction of rats following both chronic and chronic plus acute treatments. Mn-superoxide dismutase (MnSOD) activities increased in both groups, but mitochondrial GSH levels decreased only after chronic plus acute treatment. Therefore, we suggest that the increase in MnSOD activity may play an important role in the regulation of mitochondrial susceptibility against ethanol-induced oxidative stress.     

Untersuchungen über die Wirkung von Azathioprin,Cholinorotat und Phenobarbital auf Enzyme des endoplasmatischen Reticulum und Mitochondrien der Rattenleber

Summary The activity of mitochondrial and microsomal enzymes in rat liver was investigated after treatment with azathioprine, choline orotate and phenobarbital.Oral application of 25 mg azathioprine per kg body weight daily for 12 days resulted in an increase of glucuronic acid transferase activity by 250%. Cytochrome P 450 content and activity of NADPH-cytochrome-c reductase were increased by 50% and 65%, respectively. The activity of glutamate oxalacetic transaminase and succinic dehydrogenase remained unchanged. There was no effect on the microscopical appearance of the liver.After daily application of 50 mg azathioprine per kg body weight, 50% of the rats died within 8 days. The surviving animals showed a marked decrease of mitochondrial and microsomal enzyme activities and multiple parenchymal lesions in the liver and an increase in serum transaminases.Intraperitoneal application of 70 mg choline orotate per kg body weight three times daily over 12 days resulted in a decrease of the activities of glucuronic acid transferase by 42% and of cytochrome P 450 content by 25%. NADPH-cytochrome-c reductase activity was increased by 40% and glutamate oxalacetic transaminase and succinic dehydrogenase activities were increased by 20% and 50%, respectively. The histological picture remained normal. After a single dose of 250 mg choline orotate per kg body weight all rats died within 2 min. Chronic application of choline chloride equivalent to choline orotate did not alter the activities of the abovementioned enzymes. In the acute experiment carried out with the same molarity of choline chloride all animals died, showing that the acute toxic effect is due to choline and not to orotate.Oral application of phenobarbital resulted in an increase of activities of glucuronic acid transferase, cytochrome P 450, and NADPH-cytochrome-c reductase by about 400% whereas the activity of succinic dehydrogenase was reduced by 30%.The results are discussed in respect to the possible effect of these drugs in experimental liver damage and their implication for human liver disease.

     

Potential beneficial effect of naringenin on lipid peroxidation and antioxidant status in rats with ethanol‐induced hepatotoxicity

Objectives The aim was to study the effect of naringenin, a biologically active compound, on tissue antioxidant status and lipid peroxidation in ethanol‐induced hepatotoxicity in rats. Methods Rats were divided into four groups: Groups 1 and 2 received isocaloric glucose and 0.5% carboxymethyl cellulose; groups 3 and 4 received 20% ethanol equivalent to 6 g/kg daily for 60 days. In addition, groups 2 and 4 were given naringenin (50 mg/kg) daily for the last 30 days of the experiment. Key findings The results showed significantly elevated levels of serum aspartate and alanine transaminases, γ‐glutamyl transpeptidase, tissue thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and protein carbonyl content, and significantly lowered activities/levels of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione‐S‐transferase, reduced glutathione and vitamins C and E in ethanol‐treated rats compared with control rats. Administration of naringenin to rats with ethanol‐induced liver injury significantly decreased the levels of serum aspartate and alanine transaminases, γ‐glutamyl transpeptidase, tissue thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and protein carbonyl content and significantly elevated the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione‐S‐transferase, and the levels of reduced glutathione and vitamins C and E in the tissues compared with unsupplemented ethanol‐treated rats. Histological changes observed in the liver correlated with the biochemical findings. Conclusions Taken together these findings suggest that naringenin has a therapeutic potential in the abatement of ethanol‐induced hepatotoxicity.     

Induction of drug-metabolizing enzymes and toxicity of trans-stilbene oxide in rat liver and kidney

The effect of trans-stilbene oxide (TSO) on organ function and morphology and on drug-metabolizing enzymes was determined in male Sprague-Dawley rats. TSO (300 or 600 mg/kg) was administered i.p., once daily for 5 consecutive days. At a dose of 3400 mg/kg, TSO did no alter body weight, but increased liver weight. The higher dose (600 mg/kg) markedly decreased body weight. TSO treatment (300 mg/kg) induced several drug-metabolizing enzymes. Epoxide hydrolase activity was enhanced in the liver, kidney and lung. In contrast, arylhydrocarbon hydroxylase activity was not significantly altered. Glutathione S-transferase activity, with 1-chloro-2,4-dinitrobenzene as substrate, and uridine diphosphoglucuronyl transferase activity, with p-nitrophenol as substrate, were also increased in the liver and kidney after TSO treatment. It appears that TSO induces hepatic and renal enzyme activities in a similar manner. Treatment with the higher dose of TSO depressed accumulation of p-amino-hippurate by renal cortical slices and increased blood urea nitrogen concentration. Histological examination of kidney sections after treatment with TSO revealed no abnormality. The lower dose led to negligible alteration in liver and the higher dose resulted in mild to moderate hepatic cellular.     

Effect of streptozotocin on the glutathione S-transferases of mouse liver cytosol

Streptozotocin (STZ) increased the activity of mouse hepatic glutathione (GSH) S-transferases assayed with 1-chloro-2,4-dinitrobenzene. Nicotinamide administered prior to STZ prevented the hyperglycemia indicative of STZ-induced diabetes, but had no effect on the increase in GSH S-transferase activity caused by the drug. Another diabetogenic agent, alloxan, did not alter GSH S-transferase activity. Thus, streptozotocin may be increasing GSH S-transferase activity directly, and not as a result of the diabetic state the drug induces. Two transferases were characterized from mouse liver cytosol. One was a homodimer with a subunit molecular weight of about 28,000 and a pI of about 8.2. The other was also a homodimer with a subunit molecular weight of about 27,500 and a pI of about 9.2. The pI 8.2 GSH S-transferase was induced by STZ, while the pI 9.2 transferase was decreased by the drug. At least one other transferase appeared to be induced by STZ. Two other nitroso compounds, chlorozotocin and diethylnitrosamine, also increased GSH S-transferase activity, suggesting that this effect may be nitroso related.     

Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats

Cyclophosphamide is an inactive cytostatic, which is metabolised into active metabolites mainly in the liver. During bioactivation, reactive oxygen species (ROS) are also formed, which can modify the components of both healthy and neoplastic cells leading to decreased antioxidative capacity. Amifostine is a drug that can inactivate ROS. The aim of the present study was to evaluate the influence of amifostine on the antioxidative system of the liver of rats exposed to cyclophosphamide. Intraperitoneal administration of cyclophosphamide was found to decrease the activity of liver antioxidative enzymes, i.e. superoxide dismutase, glutathione peroxidase and glutathione reductase, and to increase catalase activity. Amifostine slightly influenced antioxidative enzyme activity, causing a significant increase only in superoxide dismutase activity. Co-administration of cyclophosphamide and amifostine nearly prevented changes in activities of superoxide dismutase, glutathione reductase and catalase, as well as to a high degree of glutathione peroxidase. Cyclophosphamide also evoked a decrease in the level of non-enzymatic antioxidants, such as reduced glutathione and vitamins C, E and A, as well as total antioxidant status. Administration of amifostine alone caused a significant increase in non-enzymatic antioxidant level that resulted in an increase in total antioxidant status. Administration of amifostine together with cyclophosphamide to a large extent prevented changes in the evaluated non-enzymatic antioxidative parameters, decreasing values of their concentration to the values of control group. Changes of liver antioxidative abilities during detoxification of cyclophosphamide were accompanied by intensified lipid peroxidation, manifested by an increase in concentration of products such as malondialdehyde and 4-hydroxynonenal. Amifostine caused the inhibition of lipid peroxidation in the liver of both control and cyclophosphamide-treated rats. In conclusion, our results suggest that amifostine significantly protects liver antioxidant properties from changes caused by cyclophosphamide treatment and in consequence prevents oxidative stress and phospholipid peroxidative damage.     

硒多糖、亚砷酸钠对大鼠肝微粒体酶和GSH-Px等的影响

研究了硒多糖、亚砷酸钠在体内、外对大鼠肝微粒体酶细胞色素Ｐ－４５０、ｂ５、ＮＡＤ（Ｐ）Ｈ－细胞色素Ｃ还原酶、谷胱甘肽硫转移酶（ＧＳＴ）的影响;并通过测定硒多糖、亚砷酸钠对肝谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）和脂质过氧化（ＬＰＯ）的影响,探讨了硒、砷相互作用的机理。结果表明：连续７天腹腔注射０．２ｍｇ／ｋｇ硒多糖,细胞色素Ｐ－４５０、ｂ５的含量、ＧＳＴ的活性降低（Ｐ＜０．０５）;硒多糖明显诱导ＧＳＨ－Ｐｘ的活性,降低脂质过氧化,拮抗亚砷酸钠对ＬＰＯ的作用。亚砷酸钠显著增强肝细胞脂质过氧化（Ｐ＜０．０５）,对ＧＳＨ－Ｐｘ和肝微粒体酶无明显影响     

Changes in antioxidant status and biochemical indices after acute administration of artemether, artemether-lumefantrine and halofantrine in rats

Artemether, artemether-lumefantrine, or coartem and halofantrine are alternative antimalarial drugs to chloroquine. Their efficacy and potential to delay drug resistance in falciparum malaria had led to their increased use. Although these drugs have proven to be well tolerated, there are adverse effects associated with them. This study was designed to examine the toxic potential of acute administration of these drugs in rats. Twenty-four rats were divided into four groups: group I (control) received distilled water; group II received artemether for 5 days with an initial dose of 3.2 g/kg body weight on day 1 and 1.6 mg/kg body weight on days 2-5; group III received coartem (27 mg/kg body weight/day) for 3 days, which was divided into two equal portions per day; and group IV received halofantrine (24 mg/kg body weight/day) in three equal portions. Administration of artemether, coartem and halofantrine caused significant decrease (P < 0.05) in reduced glutathione levels in the liver by 29%, 21% and 26%, respectively. In contrast, there were no significant differences (P > 0.05) in the kidney glutathione levels. Furthermore, artemether, coartem and halofantrine decreased the liver- and kidney-enzymatic antioxidant status of the animals. Precisely, artemether, coartem and halofantrine decreased liver superoxide dismutase and catalase activities by 45%, 50% and 57%; and 20%, 29% and 23%, respectively. While the kidney catalase activities were decreased by 41%, 28% and 30%, respectively, the drugs however did not produce significant effect (P > 0.05) on the kidney superoxide dismutase activities. In addition, artemether, coartem and halofantrine decreased the hepatic levels of glutathione S-transferase by 64%, 51% and 53%, respectively. Administration of artemether, coartem and halofantrine significantly increased (P < 0.05) liver and kidney lipid peroxidation levels by 67%, 50% and 81%; and 58%, 43% and 31%, respectively. This indicates that the liver is considerably more affected than the kidneys. Similarly, halofantrine treatment caused significant elevation (P < 0.05) in the levels of serum creatinine, aspartate and alanine aminotransferases and blood urea nitrogen by 73%, 66%, 61% and 63%, respectively. These data indicate that oral administration of artemether, coartem and halofantrine has adverse effects on both enzymic and non-enzymatic antioxidant status of the animals.     

Effect of gossypol on liver metabolic enzymes in male rats

The effects of gossypol on liver metabolism were examined in male rats. Gossypol acetic acid was administered to Sprague-Dawley rats intraperitoneally (i.p.) at 5 mg/kg daily, 5 days/week for 2 weeks. The rats were killed 24 h after the last injection. The liver/body weight ratio (-42%), concentration of liver glutathione (-34%), activities of liver alpha-naphthtylacetate esterase (-30%) and DNase (-39%) were significantly decreased when compared to controls. Hepatic beta-glucuronidase (+37%), RNase (+35%) and serum alkaline RNase (+23%) activities were significantly increased. No changes were found in serum transaminases (SGPT, SGOT) or in hepatic RNA and DNA concentration. Elevation of liver and serum RNase activities suggest that gossypol treatment produces some catabolic effects. The depletion of hepatic glutathione and the elevation of beta-glucuronidase activity indicate that gossypol is hepatotoxic when given at this dose for 2 weeks.