Hepatic Microsomal Lipid Peroxidation Research Articles

Antioxidant and Hypolipidemic Activities of Cinnamic Acid Derivatives.

Oxidative stress and hyperlipidemia are important factors for the initiation and progression of various cell degenerative pathological conditions, including cardiovascular and neurological diseases. A series of cinnamic acid-derived acids, such as ferulic acid, sinapic acid, 3,4-dimethoxycinnamic acid, p-coumaric acid, and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid, were esterified or amidated with various moieties, bearing different biological activities, and evaluated. The antioxidant and radical scavenging abilities of the compounds via inhibition of rat hepatic microsomal membrane lipid peroxidation, as well as their interaction with the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH), were assessed. Further, their hypolipidemic activity in vivo was tested. The majority of the obtained compounds demonstrated considerable radical scavenging and antioxidant action, with a parallel decrease in Triton-induced hyperlipidemia in rats. The (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid derivative with morpholine and 4-methylpiperidine (compounds 4 and 13, respectively) significantly decreased triglycerides and total cholesterol in the plasma of hyperlipidemic rats, with an antioxidant capacity similar to that of the antioxidant Trolox. The compounds were designed to exhibit antioxidant and hypolipidemic pharmacological actions, and this succeeded for the majority of them. Thus, such agents may be of interest in conditions and diseases implicating oxidative stress and dyslipidemia.

Ascorbic acid inhibits ferric nitrilotriacetate induction of ornithine decarboxylase, DNA synthesis, oxidative stress, and hepatotoxicity in rats

Ascorbic acid (AA) is a naturally occurring phenolic compound with antioxidant properties used in food, cosmetics, and pharmaceutical products. In this study, the effect of AA on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats has been examined. Fe-NTA alone enhances ornithine decarboxylase activity to 4.5-fold and tritiated thymidine incorporation in DNA to 3.6-fold in livers compared with the corresponding saline-treated controls. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 3.02- and 1.88-fold, respectively, at a higher dose of 2 mg AA per day per animal, compared with the Fe-NTA-treated groups. Fe-NTA treatment also enhanced the hepatic microsomal lipid peroxidation to 1.7-fold compared to saline-treated controls. These changes were reversed significantly in animals receiving pretreatment of AA. The present data shows that AA can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and hepatotoxicity in rats.

Attenuation of KBrO3‐Induced Renal and Hepatic Toxicity By Cloudy Apple Juice In Rat

The aim of the study was to evaluate a protective effect of apple juice on KBrO3-induced oxidative stress in rats. Male Wistar rats were administered apple juice per os, 10 ml/kg b.w. for 28 days. On 27 day of the experiment, some rats were given i.p. a single 125 mg/kg b.w. dose of KBrO3 . Markers of oxidative damage and clinical chemistry parameters were determined. Treatment with apple juice prior to KBrO3 challenge prevented an increase in hepatic and renal microsomal lipid peroxidation by 25 and 44%, respectively, increased the activity of antioxidant enzymes in the liver by 29 - 59% and decreased the plasma content of carbonyl groups by 19%. Aminotransferases activity in plasma was reduced by 19% and 36%, concentrations of plasma bilirubin, cholesterol and creatinine were suppressed by 21%, 16% and 26%, respectively, in rats supplemented with juice before KBrO3 injection. No protective effect of apple juice on nuclear DNA was observed. Supplementation with cloudy apple juice to some extent attenuated oxidative damage induced by KBrO3 in the liver and kidney of rats as evidenced by alterations of certain oxidative stress markers and clinical chemistry parameters.

Antioxidant capacity of flavonoids in hepatic microsomes is not reflected by antioxidant effects in vivo.

Flavonoids are polyphenolic compounds with potential antioxidant activity via multiple reduction capacities. Oxidation of cellular lipids has been implicated in many diseases. Consequently, this study has assessed the ability of several dietary flavonoid aglycones to suppress lipid peroxidation of hepatic microsomes derived from rats deficient in the major lipid soluble antioxidant, dα-tocopherol. Antioxidant effectiveness was galangin > quercetin > kaempferol > fisetin > myricetin > morin > catechin > apigenin. However, none of the flavonoids were as effective as dα-tocopherol, particularly at the lowest concentrations used. In addition, there appears to be an important distinction between the in vitro antioxidant effectiveness of flavonoids and their ability to suppress indices of oxidation in vivo. Compared with dα-tocopherol, repletion of vitamin E deficient rats with quercetin, kaempferol, or myricetin did not significantly affect indices of lipid peroxidation and tissue damage. Direct antioxidant effect of flavonoids in vivo was not apparent probably due to low bioavailability although indirect redox effects through stimulation of the antioxidant response element cannot be excluded.

Synthesis and antifungal and antioxidant properties of some new 5-substituted-4-amino(or aryl)-3-mercapto-4(H)-1,2,4-triazoles.

The synthesis and antifungal and antimicrobial evaluation of some new 5-substituted-4-amino(or aryl)-3-mercapto-4(H)-1,2,4-triazoles is reported. The involvement of the new compounds in free radical processes is also investigated and their lipophilicity is calculated and related to the determined antioxidant activity. Compounds 7a, 7b and 7c exhibited interesting antioxidant properties at concentration 0.01 mmol/l, expressed by their capacity to inhibit Fe2+/ascorbate induced hepatic microsomal lipid peroxidation, to scavenge OH.and to interact with nitrogen centered radicals such as 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH). Moreover, compound 6a showed activity against Aspergillus versicolor, possessing a MIC of 82 micrograms/ml.

Antioxidant activity of guaiazulene and protection against paracetamol hepatotoxicity in rats.

The effect of guaiazulene, a lipophilic azulene derivative widely found in nature, on radical-mediated processes is examined. The ability of guaizulene to inhibit rat hepatic microsomal membrane lipid peroxidation and to scavenge hydroxyl radicals, as well as to interact with 1,1-diphenyl-2-picrylhydrazyl radical (DPPH), was estimated. It was found that guaiazulene can inhibit lipid peroxidation very significantly, having an IC50 value of 9.8 microM. It can also scavenge hydroxyl radicals and interact with DPPH. The protection afforded by guaiazulene to rats with paracetamol-induced liver injury was also investigated. Paracetamol hepatotoxicity is caused by the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which causes oxidative stress and glutathione (GSH) depletion. Hepatic cytosolic protein, GSH, glutathione transferase and glutathione reductase levels are determined as indices of hepatic injury with or without the administration of guaiazulene. It was found that all parameters affected by paracetamol are restored to normal by guaiazulene treatment, while the administration of guaiazulene alone has no effect on the performed tests compared with the control values. It was concluded that the significant protection against paracetamol-induced GSH depletion and hepatic damage afforded by guaiazulene is probably connected with its antioxidant activity. A molecular mechanism of action of guaiazulene is suggested.

Protective effect of chokeberry on chemical-induced oxidative stress in rat

Male Wistar rats were treated with chokeberry juice per os, 10 mL/kg/day, for 28 days and a single intraperitoneal (i.p.) dose of N-nitrosodiethylamine (NDEA), 150 mg/kg, or carbon tetrachloride (CCl(4)), 2 ml/kg. The level of hepatic microsomal lipid peroxidation, expressed as thiobarbituric acid reactive substances (TBARS), was increased in animals dosed with NDEA and CCl(4). Juice pretreatment resulted in a significant decrease in TBARS by 53% and 92%, respectively. In rats administered juice alone, 50% decrease in TBARS was noted. The activities of all antioxidant enzymes were decreased in the liver of rats administered either toxicant by 29%-52% as compared to controls. Juice pretreatment resulted in an increase in the activity of catalase, glutathione peroxidase and glutathione reductase by 117%, 56% and 44%, respectively, only in rats challenged with NDEA. Although no response of plasma protein carbonyls to both toxicants was observed, the pretreatment with juice caused a 55% decrease of this parameter in CCl(4)-dosed rats. DNA damage in blood leukocytes induced by either toxicant was slightly reduced, by 24%, in the rats pretreated with juice and administered NDEA. The results of the study showed that pretreatment with chokeberry juice confers some protection against chemical-induced oxidative stress.

Antihypertensive, vasodilator and antioxidant effects of a vinifera grape skin extract

Cumulative evidence suggests that moderate wine consumption exerts a cardioprotective effect. We investigated the occurrence of an antihypertensive effect of an alcohol-free hydroalcoholic grape skin extract (GSE) obtained from skins of a vinifera grape (Vitis labrusca) in experimental rodent hypertension models. The vasodilator effect of GSE (polyphenols concentration 55.5 mg g(-1)) was also assessed in the isolated mesenteric vascular bed of Wistar rats and the antioxidant effect was studied on lipid peroxidation of hepatic microsomes. Oral administration of GSE significantly reduced systolic, mean and diastolic arterial pressure in Wistar rats with desoxycorticosterone acetate-salt and N(G)-nitro-L-arginine methyl ester (L-NAME) induced experimental hypertension. In the rat isolated mesenteric vascular bed pre-contracted with norepinephrine, bolus injections of GSE induced endothelium-dependent vasodilatation that was substantially inhibited by L-NAME, but not by indometacin, tetraethylammonium or glibenclamide. Lipid peroxidation of hepatic microsomes estimated as malondialdehyde production was concentration-dependently inhibited by GSE. In conclusion, the antihypertensive effect of GSE might be owing to a combination of vasodilator and antioxidant actions of GSE. These findings also suggest that the beneficial effect of moderate red wine consumption could be owing to an antihypertensive action induced by compounds occurring in the skin of vinifera grapes.

Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone

We investigated whether cannabidiol (CBD) and cannabidiol hydroxy-quinone (CBDHQ) generate reactive oxygen species (ROS) during metabolism with mouse hepatic microsomes. CBD and CBDHQ (91.5 μM) significantly suppressed lipid peroxidation in the mouse hepatic microsomes. CBDHQ also significantly decreased NADH-cytochrome b 5 reductase (fp 1) activity by 25% of the control activity in the hepatic microsomes, and tended to increase NADPH-cytochrome c (P450) reductase (fp 2) activity. CBDHQ also significantly inhibited superoxide dismutase and catalase activities in mouse hepatic 105,000 × g supernatant. Moreover, CBDHQ significantly increased glutathione reductase activity and significantly inhibited NAD(P)H-quinone reductase activity. CBD exhibited similar effects on these enzymes, except that cannabinoid significantly inhibited glutathione reductase activity in mouse hepatic 105,000 × g supernatant. These results suggest that CBDHQ is easily converted to the semiquinone form rather than the hydroquinone form. It was also suggested that CBDHQ and CBD were capable of generating ROS as superoxide anion radicals during their metabolism with mouse hepatic microsomes or with purified fp 2 by electron spin resonance spin trapping methods with 5,5-dimethyl-1-pyrroline- N-oxide. The present results suggest that CBDHQ formed during hepatic microsomal metabolism of CBD is capable of generating ROS and inducing cell toxicity.

Effects of the anticancer dehydrotarplatin on cytochrome P450 and antioxidant enzymes in male rat tissues

The effect of dehydrotarplatin (DTP), a new antineoplastic drug analogous to cisplatin, and its metabolite (Triacid) on the hepatic, renal and testicular CYP and antioxidant enzymes of male rats was investigated. The rats were treated i.p. with a single dose of DTP (25 mg kg(-1) day(-1)) or Triacid (17.5 mg kg(-1) day(-1)) and analysed 3 or 7 days post treatment. Three days after treatment, both drugs reduced body and liver weights, which partially recovered the control level after 7 days. DTP and, to a less extent, Triacid caused a depletion of plasmatic testosterone content and a down regulation in the liver of androgen dependent male specific CYP 2C11, but not of CYP 1A and 2E1, as determined by a significant decrease of 2alpha- and 16alpha-testosterone hydroxylase activities (markers for CYP 2C11) and of apoprotein immunoreactive with anti-rat CYP 2C11 antibodies. However, the activity of testicular 17alpha-progesterone hydroxylase, a key reaction in steroidogenesis, was not altered by these drugs. The DTP and Triacid administration did not cause any alteration of the plasmatic urea nitrogen and creatinine, known as markers of kidney toxicity. However, treatment with DTP, not Triacid, either 3 and 7 days post treatment, caused in the kidney microsomes a significant increase of the total CYP content, the CYP 4A-dependent (omega)- and (omega - 1)-lauric acid hydroxylase activities and apoprotein immunoreactive with anti-rat CYP 4A1. The present study also examined the enzymatic antioxidant status of kidney and liver. Neither DTP nor Triacid administration induced, with respect to control values, any alteration of hepatic and renal glutathione reductase, glutathione S-transferase, catalase, superoxide dismutase activities, hepatic GSH level and renal microsomal lipid peroxidation level. Among the antioxidant enzymes assayed, only the renal activity of glutathione peroxidase was significantly increased after DTP but not Triacid treatment. These results indicate that DTP at a dose of 25 mg/kg and Triacid cause a feminization of the CYP enzymes in male rat liver similar to that reported for cisplatin when administered at a low dose (5 mg/kg). However, unlike cisplatin, DTP and its metabolite were unable to enhance BUN and creatinine and cause any depression of CYP activities and antioxidant enzymes in the kidney, suggesting that DTP may have low or even no potential in inducing nephrotoxicity.

Antioxidant and radical scavenging effect of different parts of four Turkish Juniperus species

The comparative antioxidant potential of J. drupacea, J. oxycedrus, J. foetidissima and J. excelsa leaf and fruit water extracts were studied. Their antioxidant activities were evaluated by the 1, 1-diphenyl-2-picrylhydrazyl (DPPH) method and non-enzymatic rat hepatic microsomal lipid peroxidation method. Various antioxidant activities were compared with standard antioxidant vitamin E (α-tocopherol). Fruit and leaf extracts of J. Durapacea (IC50; 24µg/ml; IC50; 35µg/ml, respectively) and J. foetidissima (IC50; 33.5µg/ml; IC50; 26µg/ml, respectively) were found to be a good scavenger of DPPH radical when compared to vitamin E (IC50; 13µg/ml). J.oxycedrus and J. excelsa fruit extracts exhibited the weakest effect on DPPH radical with IC50 values of 115 and 104µg/ml, respectively, compared with α-tocopherol.

Chemopreventive activity of glycyrrhizin on lead acetate mediated hepatic oxidative stress and its hyperproliferative activity in Wistar rats

Lead is a pervasive environmental pollutant with no beneficial biological role and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study we have evaluated the chemopreventive effect of glycyrrhizin on lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related alterations in rats. Lead acetate (100 mg/kg bwt., i.p.) enhanced lipid peroxidation with concomitant reduction in glutathione, glutathione reductase, glutathione- S-transferase and glutathione peroxidase activities. There was an increase in the levels of transaminase enzymes and LDH. Lead acetate treatment also enhanced ornithine decarboxylase (ODC) activity and [ 3H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with glycyrrhizin (150 and 300 mg/kg bwt., orally) resulted in a significant decrease in hepatic microsomal lipid peroxidation ( P < 0.001) and increase in the level of GSH content ( P < 0.001) and its dependent enzyme. There was significant reduction in the levels of SGPT, SGOT and LDH ( P < 0.001). A significant inhibition in ODC activity and DNA synthesis ( P < 0.001) was also observed. On the basis of the above results it can be hypothesized that glycyrrhizin is a potent chemopreventive compound against lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related responses in rats.

293 EFFECT OF GUAIAZULENE ON IN VITRO BOVINE EMBRYO PRODUCTION

The substrates used in in vitro embryo production (IVP) mimic the in vivo fluids in which oocytes mature, oocytes are fertilized, and the early embryos develop (follicular and oviductal fluid). It is well established that oxidative stress negatively affects in vitro culture (IVC) outcomes. Guaiazulene (G) is a component of chamomile species oil with known antioxidant properties. In the present study, all IVP media were modified by the addition of G solutions so that the former exhibited a total protection against induced lipid peroxidation (TPaLP) similar to that of the respective in vivo environment. The IVP outcomes were then compared between G-processed and control oocytes. Bovine preovulatory follicular (BF) and oviductal (BO) fluid samples were collected from 10 Holstein 4- to 5-year-old cows in estrus. TPaLP was assessed according to the samples&amp;apos; ability to inhibit rat hepatic microsomal lipid peroxidation, by determination of the 2-thiobarbituric acid reactive material. TPaLP (mean % � SEM) of the BF and BO were 70.63 � 10.03 and 16.33 � 4.33, respectively, whereas those of the IVP [in vitro-matured (IVM), in vitro-fertilized (IVF), and IVC] media were lower (17.94 � 1.66, -1.82 � 0.78, and 14.57 � 1.26, respectively). TPaLP of the 0.1 mM G-modified IVP medium increased to 67.2 � 5.85, 19.98 � 2.49, and 69.19 � 6.22, respectively. A total of 2041 class A oocytes were used. The proportion of cleavage, early embryo development (embryos with more than 4 cells), or both after IVP (18 h IVM–5% CO2 in air, and 18 h IVF, 48 h IVC–5% CO2, 10% O2, 85% N) in the presence of G (n = 1237) during each of the IVP phases or any possible combination of IVP phases was compared with the respective control (C, n = 804). Statistical analysis was performed by a chi-squared test; P &amp;lt; 0.05 was considered significant. G improved cleavage and embryo development rates when present during IVM (79.4 and 57.8% vs. 64.5 and 38.2% for C) or both IVM and IVC (78.0 and 60.7% vs. 57.8 and 36.5%, respectively). When present only during 18 h of IVF, G had no effect on embryo production. However, an increased embryo development rate resulted from the combined exposure to G during IVF and IVM (56.4 vs. 29.6%), during IVF and IVC (55.3 vs. 35.5%), or at all IVP phases (56.6 vs. 34.9%). The latter effect resembled the one obtained after G addition only to the IVC medium (62.5 vs. 39.7%, respectively). We concluded that the addition of G to IVP substrates, at concentrations that mimic the in vivo TPaLP conditions, could promote bovine IVP efficiency.

고려홍삼으로부터 분리한 수용성 갈변물질의 항산화 활성

The purpose of this study was to investigate the biological activities of water soluble browning reaction products(WS-BRPs) isolated from korean red ginseng. Antioxidative activities of WS-BRPs were examined with the various systems. Three different fractions prepared by osmolytic treatment of WS-BRP(fraction L, S-1 and S-2) were found to have an ability to donate hydrogen to DPPH and also exhibited the inhibitory activities in lipid peroxidation, consumption of oxygen and protein oxidation of mitochondrial fraction. Especially, L had the strongest activity of these three WS-BRPs in scavenging free radicals. Lipid peroxidation showed the antioxidant effect on linoleic acid oxidation inhibition ratio of 22.5%, 31.7%, 31.9% and 33.5%, respectivity. And the consumption of oxygen was strongly inhibited by 49.52%, 62,44,97.54%. But three WS-BRPs shuwed weak inhibitory activity on lipid peroxidation in rat hepatic microsomes.

Effect of Dietary High-Oleic-Acid Oils that are Rich in Antioxidants on Microsomal Lipid Peroxidation in Rats

In contrast to other metabolic functions, the role of dietary antioxidants and oil on microsomal lipid oxidation has been less extensively studied. This study examines ascorbate-Fe(2+) and NADPH-induced lipid peroxidation of hepatic microsomes of rats that were fed for three weeks high-oleic-acid oils (high-oleic sunflower oil, HOSO; olive oil, OO; or olive pomace oil, OPO) containing different concentrations of the antioxidants alpha-tocopherol, erythrodiol, and oleanolic acid. The fatty acid composition of hepatic microsomes of Wistar rats that were fed for three weeks with the above-mentioned oils had lower proportions of C16:0, C18:2n6, and C22:6n3 and higher proportions of C18:0 and C18:1n9 than rats fed the control diet. Light emission by hepatic microsomes increased, in the first 180 min, 2-fold after ascorbate-Fe(2+) addition compared with NADPH addition. Both increases were less pronounced in microsomes of OPO-fed rats and to a smaller extent in microsomes of OO-fed rats. Smaller increases in light emission were associated positively with higher concentrations of dietary alpha-tocopherol, erythrodiol, and oleanolic acid but were not associated with changes in fatty acid composition of hepatic microsomes. Addition of alpha-tocopherol, erythrodiol, or oleanolic acid decreased light emission of hepatic microsomes with a greater inhibition in microsomes of rats fed the control diet. Our data suggest that erythrodiol and oleanolic acids partly explain the protective effect of dietary OPO on microsomal lipid peroxidation in rats.

Inhibition of tumour promotion in mouse skin by extracts of rooibos ( Aspalathus linearis) and honeybush ( Cyclopia intermedia), unique South African herbal teas

The modulating effect of ethanol/acetone (E/A) soluble fractions, prepared from methanolic extracts of processed and unprocessed rooibos ( Aspalathus linearis) and honeybush ( Cyclopia intermedia) as well as green ( Camellia sinensis) teas was established in a two-stage mouse skin carcinogenesis assay. Topical application of the tea fractions prior to the tumour promoter, 12- O-tetradecanoylphorbol-13-acetate (TPA), on ICR mouse skin initiated with 7,12-dimethylbenz[ a]anthracene (DMBA) suppressed skin tumorigenesis significantly ( P<0.001) with the green tea E/A fraction exhibiting a 100% inhibition, unprocessed honeybush 90%, processed honeybush 84.2%, processed rooibos 75% and unprocessed rooibos 60%. The green tea fraction, with the highest flavanol/proanthocyanidin content, also exhibited the highest protective activity (99%) against hepatic microsomal lipid peroxidation, and completely inhibited skin tumour formation. Differences in the flavanol/proanthocyanidin and flavonol/flavone composition and/or non polyphenolic constituents are likely to be important determinants in the inhibition of tumour promotion by the herbal tea E/A fractions in mouse skin.

Antioxidant activity of novel indole derivatives and protection of the myocardial damage in rabbits.

Novel indole derivatives containing a triazole moiety (1a-d, 2a-c) were synthesized as lead compounds with interesting pharmacological profiles. Their antioxidant activity was investigated on in vitro non-enzymatic rat hepatic microsomal lipid peroxidation. All compounds showed significant effect in the above assay. The effect depended mainly on the attachment position of the triazole moiety on the indole nucleus. The most potent antioxidant derivatives la, 1c and 1d were tested for their protective ability against the oxidative damage of the myocardium after ischemia-reperfusion, in male rabbits which were subjected to 30 min regional ischemia followed by reperfusion. The tested antioxidant compounds 1a, 1c and 1d were continuously infused for 30 min starting at 10th min of ischemia and lasted at 10th min of reperfusion. The concentration of malondialdehyde (MDA, a marker of lipid peroxidation) and hemodynamic parameters (blood pressure and heart rate) were measured in the baseline, at 20th min of the sustained ischemia, 1st and 20th min of reperfusion. It was found that the examined compounds la, 1c and 1d reduced significantly the level of MDA in rabbits under ischemia-reperfusion and proved to be promising substances for further evaluation of anti-ischemic properties.

Antioxidant status and hepatic lipid peroxidation in chloramphenicol-treated rats.

The present study reports the enzymatic and non-enzymatic antioxidant status and hepatic microsomal lipid peroxidation in chloramphenicol treated rats. Chloramphenicol at a dose of 28 mg/kg body weight orally administered to rats increased the activity of cytosolic superoxide dismutase by 63% while the activities of glutathione peroxidase and catalase were decreased by 57% and 44%, respectively. In vitro, chloramphenicol altered the activities of these enzymes though not as pronounced as the effect of the drug on the enzymes in vivo. The levels of serum vitamins A, C and beta-carotene were significantly decreased following chloramphenicol treatment. Microsomal lipid peroxidation was markedly and significantly increased by chloramphenicol treatment. The drug elicited 69% and 71% increases in the levels of malondialdehyde and lipid hydroperoxide respectively. Glutathione level and glutathione S-transferase activity were decreased by 42% and 58%, respectively, compared to untreated controls. Overall, the results of the present investigation indicate alteration of enzymatic and nonenzymatic antioxidant status and induction of lipid peroxidation by chloramphenicol. The clinical implications in the detoxification of toxic metabolites of lipid peroxidation caused by chloramphenicol warrant co-administration with antioxidant vitamins in chloramphenicol treatment regimen.

Influence of amodiaquine treatment on microsomal lipid peroxidation and antioxidant defense systems of rats.

The effects of single and multiple doses amodiaquine treatment on enzymatic and non-enzymatic antioxidant profiles and hepatic microsomal lipid peroxidation were investigated in rats. Treatment of rats with 10 mg/kg (single dose) amodiaquine resulted in 10% and 63% increases, respectively in the activities of liver superoxide dismutase and glutathione peroxidase (P<0.01), while the activity of liver catalase was significantly reduced by 26% compared to control. The levels of serum vitamins A, C and beta-carotene were lowered following amodiaquine treatment. Following multiple dose (10 mg/kg for 4 consecutive days) amodiaquine treatment, activities of superoxide dismutase and glutathione peroxidase were increased by 30% and 133% respectively while catalase activity was decreased by 45%. Similarly, serum vitamins A, C and beta-carotene levels were markedly decreased. In the single dose study, the levels of malondialdehyde and the activity of glutathione S-transferase were increased by 15% and 44% respectively while the reduced glutathione was decreased by 25% compared to control. Malondialdehyde level was highly increased (P<0.001) by 71% following multiple amodiaquine treatment. Reduced glutathione was decreased by 55% and unlike in the single dose study, activity of glutathione S-transferase was decreased by 60% compared to control. The activities of serum aspartate amino transferase, alanine amino transferase, ornithine carbamyl transferase and gamma-glutamyl transferase were significantly increased by both single and multiple doses of amodiaquine treatment (P<0.01). The alteration in enzymatic and non-enzymatic antioxidant defense system, increase in lipid peroxidation and increase in the activities of serum enzymes following amodiaquine treatment suggests damage to the liver and could subject the organ to further oxidative stress. The relevance of this to continuous exposure to amodiaquine therapy should be considered.

Effect of three structurally related antimalarial drugs on liver microsomal components and lipid peroxidation in rats.

Changes in microsomal drug oxidizing enzymes, microsomal lipids, hepatic glutathione (GSH), glutathione S-trans-ferase (GST) and malondialdehyde (MDA) formation following administration of rats with therapeutic doses of three structurally related antimalarial drugs, amodiaquine (AQ), mefloquine (MQ) and halofantrine (HF) were investigated. There was a significant decrease in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase in AQ, MQ and HF treated rats. AQ elicited the greatest effect with 50, 37 and 67% reductions in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase, respectively. All the drugs prolonged hexobarbital-sleeping time to varying extents. The three drugs increased significantly the cholesterol per phospholipid ratio. AQ, MQ and HF decreased significantly the GSH level, GST activity and increased the formation of MDA. The results indicate that the alterations in hepatic microsomal components and lipid peroxidation caused by the antimalarials are related to the structural differences in the compounds.