Biochemical indicators of hepatotoxic effects of pesticides

Pesticides can cause damage to man and beneficial organisms. Some sub-lethal effects of pesticides were studied in birds with a view to identifying characteristic biochemical responses that may be useful for the monitoring of exposure to sub-lethal levels in the field. Pesticides were used: demeton-S-methyl, (DSM), chlorpyriphos, chlorfenviphos, triazophos, pirimicarb, methiocarb and permethrin. Blood was collected before dosing, and 2, 6, 24, 48 and 72 hours after the treatment from the brachial vein of birds. Enzyme activities were assayed in the plasma or serum samples obtained. The assays used were GOT, MDH, GDH, SDH, GAMMA GT and ChE. The results showed an increase in plasma and serum GOT and gamma-GT levels were found in all animals treated with the previous pesticides. The level of ChE increased in birds after treatment with permethrin. It was concluded that the pesticides cause structural and functional changes in the liver and also, the measurement of the previous parameter activities may be useful for assessing exposure and sub-lethal effects of pesticides on the wildlife.     

Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.

Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.     

The Influence of Methionine, Selenomethionine, and Vitamin E on Liver Metabolic Pathways and Steatosis in High-Cholesterol Fed Rabbits

Significant disorders of liver metabolic pathways enzymes after high-cholesterol diet could give information on liver steatosis development. This process could probably also be inhibited by some compounds, as examined in rabbits. Forty-two male rabbits were served a high-cholesterol diet (2 g%) (0.67 g/kg b.m./24 h) with addition of d,l-methionine (70 mg/kg b.m./24 h) or seleno-d,l-methionine (12.5 μg/kg b.m./24 h) or α-tocopherol (10 mg/kg b.m./24 h) for 3 months to compare the protection effect of used compounds on liver metabolism and steatosis. At the beginning and every month, blood was taken. After the experiment was completed, livers were dissected for histological examinations. The concentration of total cholesterol (t-CH), triacylglycerol (TG), and the activities of aldolase (ALD), sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were determined. Plasma t-CH and TG concentrations were significantly higher in all experimental groups vs control group. Blood serum AST and ALT activities did not undergo change but there were observed not significant increase in the CH group vs control group. Activities of SDH, GLDH, and LDH increased in blood serum and decreased in the liver in all experimental groups. Activities of LDH and SDH increased in the liver in the CH+Met group vs CH group. ALD activity decreased in the liver only in the CH and CH+Se groups. This data support a lipotoxic model of cholesterol-mediated hepatic steatosis. Prolonged administration of high-cholesterol diet not only disturbs the structure of cell membranes, which is expressed by decreased activity of enzymes in the liver and the migration of those enzymes to plasma but as well leads to steatosis of the liver, which has been confirmed by histological examinations. The applied compounds appear to have a varying influence upon the activity of enzymes determined in serum and liver. Obtained results showed a beneficial influence of methionine and vitamin E supplementation on liver steatosis development.     

Change in liver and plasma ceramides during D-galactosamine-induced acute hepatic injury by LC-MS/MS

In fulminant hepatic failure, various toxins causing multi-organ failure increase in plasma. As a novel toxin, ceramide, a well-studied lipid mediator of apoptosis, levels were determined by LC-MS/MS in the liver and plasma of D-galactosamine-intoxicated rats. 18 and 24h after intraperitoneal administration of D-galactosamine (1g/kg body weight) to rats, fulminant hepatic failure occurred as evidenced by a severe elevation in plasma GOT and GPT. The liver concentration of minor ceramide components (C18:0, C20:0, C22:1, C22:0, and C24:2) increased significantly compared to that in the control group that was given saline. The plasma concentration of major ceramides (C24:0, C24:1, C16:0, C22:0, C22:1, and C18:0) increased 24h after administration of D-galactosamine and the total ceramide concentration was also increased to 3.6 times that in the control. In conclusion, the increased concentrations of ceramides in plasma during fulminant hepatic failure may be one of important toxins causing damage in other organs including the brain and kidney.     

Effect of metal mixtures on activity of two respiratory enzymes and their recovery in Oreochromis mossambicus (Peters).

Effects of sublethal doses of metal (Cu, Cd, Zn) mixtures on the activities of key respiratory enzymes (succinate dehydrogenase, SDH and glyceraldehyde dehydrogenase, GDH) and their recovery following withdrawal of treatments were studied in the freshwater fish O. mossambicus. On the basis of 96 hr LC50 Cu was highly toxic followed by Zn and Cd, and the trimetal combination (Cu+Zn+Cd) was extremely toxic than any other combination; combination of Zn+Cd was least toxic. A significant gradual decrease in SDH with a concomitant increase in GDH activity observed in liver, brain, muscle and gill of animals exposed to metal suggest a metabolic shift from aerobiosis to anaerobiosis due to metal action. Exposed individuals when transferred to metal impoverished water showed an improvement in SDH activity and decline in GDH activity suggesting slow reversal to aerobic metabolism. O. mossambicus needs more time for complete recovery.     

Induction of glutamate dehydrogenase in the ovine fetal liver by dexamethasone infusion during late gestation

Glucocorticoids near term are known to upregulate many important enzyme systems prior to birth. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that catalyzes both the reversible conversion of ammonium nitrogen into organic nitrogen (glutamate production) and the oxidative deamination of glutamate resulting in 2-oxoglutarate. The activity of this enzyme is considered to be of major importance in the development of catabolic conditions leading to gluconeogenesis prior to birth. Ovine hepatic GDH mRNA expression and activity were determined in near-term (130 days of gestation, term 147 +/- 4 days) control and acutely dexamethasone-treated (0.07 mg(-1) hr(-1) for 26 hr) fetuses. Dexamethasone infusion had no effect on placental or fetal liver weights. Dexamethasone infusion for 26 hr significantly increased hepatic GDH mRNA expression. This increased GDH mRNA expression was accompanied by an increase in hepatic mitochondrial GDH activity, from 30.0 +/- 7.4 to 58.2 +/- 8.1 U GDH/U CS (citrate synthase), and there was a significant correlation between GDH mRNA expression and GDH activity. The generated ovine GDH sequence displayed significant similarity with published human, rat, and murine GDH sequence. These data are consistent with the in vivo studies that have shown a redirection of glutamine carbon away from net hepatic glutamate release and into the citric acid cycle through the forward reaction catalyzed by GDH, i.e., glutamate to oxoglutarate.     

Enzyme Activities in Urtica dioica: Effects of Daylength and Leaf Age on Glutamate Dehydrogenase, Aspartate Aminotransferase and Alanine Aminotransferase

Enzymes, important to protein synthesis, were investigated in young and old leaves of Urtica dioica. The plants, divided into two groups, were exposed to either 18-hour or 12-hour photo-periods. One group of plants from each photoperiodic regime was subjected to an irradiance of 28 W × m^-2, and the other group of plants to 42 W × m^-2. The enzymes investigated were glutamate dehydrogenase (GDH), aspartate aminotransferase (glutamate-oxaloacetate transaminase, GOT), and alanine aminotransferase (glutamate-pyruvate transaminase, GPT), GDH and GOT were determined by means of electrophoretic separation on polyacrylamide and spectrophotometric measurements. GPT was determined only by the latter method. Plants exposed to 18-hour photoperiods showed much higher GDH activity than did those exposed to 12-hour photoperiods. The activity of GDH also increased with leaf age. Besides one uniform NAD⁺-dependent GDH, two other NAD⁺-independent enzymes, showing GDH activity, were identified on polyacryl-amide gel electrophoresis. The distribution of NADH and NAD⁺-dependent GDH activity between young and old leaves was similar under different growth conditions. The activity of GOT was insensitive to environmental changes. The results regarding GPT indicate that this enzyme responded to different photoperiods in the same way as GDH. A correlation coefficient of 0.928 was obtained for the relationship between GDH and GPT activity.     

Diurnal changes in liver and plasma lipids of choline-deficient rats

Early effects of choline deficiency were studied in rats. Nonphospholipid ("neutral lipid") and phospholipid were measured in plasma and in three fractions of a liver homogenate: sediment, supernatant fraction, and "floating fat." A single choline-deficient meal caused significant aberrations from the typical diurnal changes observed in the lipid fractions of the controls. These changes occurred in the following sequence: (a) failure of phospholipid to increase, after feeding, in the sediment fraction; (b) increase of neutral lipid, compared with controls, exclusively in the floating fraction; and (c) failure of neutral lipid to return to control levels. The rate of accumulation of neutral lipid increased during the first 4 days of deficiency. The occurrence of NADH-cytochrome c dehydrogenase in the floating fat and the absence of succinate dehydrogenase activity point to microsomal origin of the floating fat. Early effects of choline deficiency on plasma lipids were limited to phospholipid, and occurred later than changes in the liver. Plasma nonphospholipid levels were unchanged during the first 2 days; this does not support impaired secretion or transportation of glyceride as the cause of fatty liver in the early stages of choline deficiency.     

Deregulation of hepatic lipid metabolism associated with insulin resistance in rats subjected to chronic monocrotophos exposure

In our previous study, we demonstrated the potential of monocrotophos (MCP), an organophosphorus insecticide (OPI), to induce glucose intolerance, insulin resistance (IR), and dyslipidemia with hyperinsulinemia in rats after chronic exposure. As hyperinsulinemia is likely to exert an impact on hepatic lipid metabolism, we carried out this study to establish the effect of chronic MCP exposure (0.9 and 1.8 mg/kg/day for 180 days) on hepatic lipid metabolism in rats. The state of IR induced by MCP in rats was associated with an increase in the liver lipid content (triglyceride and cholesterol) and expression levels of sterol regulatory element‐binding proteins, PPARγ, acetyl‐CoA carboxylase, and fatty acid synthase in the liver. Similarly, activities of key enzymes (acetyl‐COA carboxylase, fatty acid synthase, lipin 1, malic enzyme, glucose‐6‐phosphate dehydrogenase, and glycerol‐3‐phosphate dehydrogenase), which regulate lipogenesis, were enhanced in livers of pesticide‐treated rats. A strong correlation was observed between insulin levels, hepatic lipid content, and plasma lipid profile in treated rats. Our study suggests that long‐term exposure to OPIs not only has a propensity to induce a state of hyperinsulinemic IR, but it is also associated with augmented hepatic lipogenesis, which may explain dyslipidemia induced by chronic exposure to MCP.     

Early effects of feeding excess vitamin A: mechanism of fatty liver production in rats

Oral administration of vitamin A (30,000 IU daily for 2 days) to young rats caused a marked increase in hepatic glycogen, cholesterol, and glycerides, while hepatic phospholipid content remained almost unaltered. In an examination of the pathogenesis of the lipid accumulation, it was found that more glucose-(14)C was incorporated into liver lipids in vitamin A-fed rats, whereas incorporation of glucose-(14)C and dl-glycine-(14)C into liver protein remained unaltered. The increase in glucose-(14)C incorporation was confined to the glyceride-glycerol portion of the lipids; incorporation into liver fatty acids was inhibited. Plasma free fatty acid concentrations were elevated. It is postulated that in the vitamin A-fed rats, increased accumulation of lipids in the liver is caused by a stimulation of fatty acid mobilization from adipose tissue and enhanced formation of glycerophosphate through glycolysis, with consequent increase in the glyceride synthesis in the liver. The weight of the adrenals was increased, whereas cholesterol concentration in the gland was decreased, after administration of vitamin A to rats. This indicates adrenocortical stimulation. Interestingly enough, vitamin A feeding did not affect either the level of liver lipids or of plasma FFA in adrenalectomized rats.     

Androgenic control of hepatic mitochondrial metabolism in an apoda, Gegenophis carnosus (Beddome).

In vivo administration of testosterone significantly stimulated the activities of cytochrome oxidase, alpha-glycerophosphate dehydrogenase (alpha-GPDH), succinate dehydrogenase (SDH) and adenosine triphosphatase (Mg2+ ATPase), in mitochondria isolated from the liver of G. carnosus. Administration of dehydroepiandrosterone and androstenedione while significantly stimulated the activities of cytochrome oxidase and alpha-GPDH, did not change that of SDH and Mg2+ ATPase. Simultaneous injections of testosterone and actinomycin D or chloramphenicol prevented the testosterone-stimulated activities of all the oxidative enzymes studied. The results clearly document the important stimulatory role of androgens in the regulation of hepatic mitochondrial metabolism in G. carnosus.     

The ontogenesis of catabolic abilities and energy metabolism during endogenous nutritional periods of tongue sole,Cynoglossus semilaevis

The ontogenesis of catabolic abilities and energy metabolism during endogenous nutritional periods of tongue sole was investigated. In this work, trypsin-like proteases (TRY) and triglyceride lipase (LIP) activities were measured to assess the capacities to catabolize proteins and lipids, respectively. Meanwhile, specific enzymes including pyruvate kinase (PK), glutamic oxalo acetic transaminase (GOT) and glutamate dehydrogenase (GDH), and hydroxyacyl CoA dehydrogenase (HOAD) as well as their ratios were assayed to evaluate the abilities to use energy substrates of carbohydrates, amino acids and fatty acids, respectively, for energy production. In addition, activities of citrate synthase (CS) and lactate dehydrogenase (LDH) and LDH/CS ratio were calculated to analyse the evolution of aerobic and anaerobic pathways. The study found that hatching occurred at 38.8 h after fertilization (HAF), mouth-opening day of eleuteroembryo appeared at 3 days after hatching (DAH), and the most rapid embryonic growth was observed in blastula stage before hatching. Enzymatic assay revealed that except for PK which appeared in cleavage stage onwards, all the other enzymes functioned after fertilization, preparing well for the coming embryogenesis of tongue sole. By comparing the average specific activity of enzyme in each period, it can be found that the highest value occurred at 3 DAH (for TRY, LIP, PK and LDH), 2 DAH (for GDH), fertilized egg (for GOT) and segmentation stage (for HOAD and CS), and the lowest value occurred at fertilized egg (for HOAD, CS and GDH), cleavage stage (for TRY, PK and LDH), gastrula stage (for GOT) and hatching day (for LIP). Based on the changeable patterns of metabolic enzymatic activities and ratios, it is concluded that metabolic capacities on three energy substrates displayed stage-specific traits, and the dominant energy substrate was fatty acids before segmentation stage, amino acids until hatching day and carbohydrate during eleuteroembryo period. As for energy production mode, aerobic pathway appeared to increase greater in fertilized egg and gastrula stage, whereas anaerobic pathway played a predominant role during cleavage stage, blastula stage, segmentation stage and eleuteroembryo stage. These results are valuable to elucidate the nutritional requirements of embryonic stages in tongue sole and to further understand their energy metabolic mechanisms.     

Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats

In a recent study in rats, alanine aminotransferase (ALT), the preferred plasma biomarker of hepatocellular injury in rats, was ineffective at detecting marked hepatic necrosis produced by acetaminophen (Human and Experimental Toxicology 19, 277-83, 2000). In contrast, glutamate dehydrogenase (GLDH) was markedly elevated. Accordingly, these enzymes were comprehensively evaluated as plasma biomarkers of hepatocellular injury in rats using several other models of hepatic injury, including partial hepatectomy and exposure to methapyrilene, dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643. Other enzymes also evaluated were aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH), and the hepatobiliary marker alkaline phosphatase (ALP). Compared to plasma ALT increases, plasma GLDH increases were up to 10-fold greater, up to 3-fold more persistent, and occurred at times following hepatocellular injury when plasma ALT was not increased. Plasma GLDH activity was not inhibited by the test compounds, whereas ALT was substantially inhibited by both isoniazid and lead nitrate. While plasma GLDH activity was unaffected by induction, ALT was induced by cyproterone and dexamethasone, and ALP was induced by Wyeth-14643 and partial hepatectomy. GLDH was concluded to be a more effective biomarker of acute hepatic injury than ALT, AST, SDH or ALP in the rat, based primarily on the large increase following hepatocellular injury, prolonged persistence in the blood following injury, high sensitivity for detection of injury (including pre-necrotic injury), high tissue specificity, and lower susceptibility to inhibition or induction.     

Evaluation of oxidative stress based on lipid hydroperoxide, vitamin C and vitamin E during apoptosis and necrosis caused by thioacetamide in rat liver

After 12 h of thioacetamide (500 mg/kg body weight) administration to rats, the activity of caspase-3-like protease in the liver increased significantly compared to that in the control group. In plasma, the activity of caspase-3 was barely detectable in the control rat, but had increased significantly after 24 h of drug administration along with a dramatic increase in GOT. These results indicate that thioacetamide causes apoptosis in the liver by activating caspase-3, which is released to plasma by successive necrosis. At 24 h, the concentration of liver lipid hydroperoxides, a mediator of radical reaction, was 2.2 times as high as that of control rats. After 12 and 24 h of thioacetamide administration, the liver concentrations of vitamins C and E decreased significantly. The decrease of antioxidants and formation of lipid hydroperoxides 24 h after thioacetamide administration support the view that extensive radical reactions occur in the liver during the necrotic process.     

Changes in activity levels of glutamate dehydrogenase and two transaminases of maternal liver during reproduction and after administration of oestradiol and progesterone in Zoarces viviparus (L.)

The enzyme activity per unit liver wet weight, the specific activity and the total liver activity level of glutamate dehydrogenase (GDH) and two transaminases (GOT and GPT) were studied during vitellogenesis and pregnancy. A steady level of activity was observed during the short summer vitellogenesis and during early pregnancy. During mid-term pregnancy in October the activity level significantly increased.
Administration of 5 and 100 μg oestradiol increased serum vitellogenin, total liver protein and the liver somatic index during late pregnancy. Oestradiol decreased activity and specific activity of the enzymes. However, expressing activity as total hepatic enzyme activity units in fish of standard body weight oestradiol had no effect.     

Glutamate dehydrogenase from Pisum sativum L.

A 2–8-fold increase in the activity of glutamate dehydrogenase (GDH), accompanied by an alteration of the GDH isoenzyme pattern, was observed in detached pea shoots floated on tap water (preincubated shoots). Sugars supressed the process, whereas NH ₊ ⁴ and various metabolites as well as inhibitors of energy metabolism and protein synthesis were ineffective. The subcellular distribution pattern revealed evidence that the GDH isoenzymes are exclusively located in the mitochondrial matrix. The alterations in GDH activity occurring in preincubated shoots are restricted to the mitochondria.An experimental device suitable for studying the GDH function in isolated intact mitochondria has been established. Using [¹⁴C] citrate as the carbon source and hydrogen donor, the mitochondria synthesized considerable amounts of glutamate upon addition of NH ₊ ⁴ . The rates of glutamate formation in dependency of increasing NH ₊ ⁴ levels follow simple Michaelis-Menten kinetics. Half-saturation concentrations of NH ₊ ⁴ of 3.6±1.2 mM; 1.9±0.06 mM and 1.6±0.1 mM were calculated for the mitochondria isolated from pea shoots, roots, and preincubated shoots, respectively. The results are discussed in relation to the possible role of GDH in NH_+/4 assimilation at elevated intracellular NH_+/4 levels.Abbreviations GDH Glutamate dehydrogenase - MDH malate dehydrogenase - GOT aspartate aminotransferase - SDH succinate dehydrogenase - HEPES 4-(2-hydroxyethyl)-1-piperazineethan-sulfonic acid - BSA bovine serum albumin - TPP thiamine pyrophosphate - DNP 2,4-dinitrophenol - CCCP carbonyl cyanide m-chlorophenylhydrazone - DCPIP 2,6-dichlorophenolindophenol Dedicated to Professor Dr. Maximilian Steiner on the occasion of his 75th birthday     

p-Aminophenol-induced hepatotoxicity in hamsters: role of glutathione

p-Aminophenol (PAP) is a widely used industrial chemical and a known nephrotoxin. Recently, it was found to also cause hepatotoxicity and glutathione (GSH) depletion in mice. The exact mechanism of liver toxicity is not known. The aims of this study were to determine whether PAP can cause acute hepatotoxicity in hamsters and to further investigate the role of GSH in PAP-induced toxicity. PAP was administered ip to hamsters in doses of 200-800 mg/kg. Liver damage at 24 h after PAP administration was assessed by elevations in plasma enzyme activities and histopathologic examination. GSH and cysteine (Cys) levels in liver at 4 h were determined by HPLC. PAP decreased hepatic GSH concentration to 8% and Cys to 30% of vehicle control values. It increased plasma glutamic pyruvic transaminase (GPT) activity by 47-fold and sorbitol dehydrogenase (SDH) activity by 113-fold. PAP also caused severe centrilobular hepatocellular necrosis. 2(RS)-n-Propylthiazolidine-4(R)-carboxylic acid (PTCA), a Cys precursor, attenuated the PAP-induced decreases in hepatic sulfhydryl levels; GSH and Cys were 39% and 78% of vehicle controls, respectively. PTCA also attenuated the PAP-induced elevations in plasma enzyme activities and hepatic necrosis. It was concluded that PAP hepatotoxicity is associated with depletion of hepatic GSH and can be prevented by PTCA.     

Glutamic Dehydrogenase and Glutamic-oxaloacetic Transaminase in Apple Tree Tissues

A technique is described whereby active preparations of glutamic dehydrogenase (GDH) and glutamic-oxaloacetic transaminase (GOT) can be obtained from all apple tree tissues using a hand-operated coffee mill. The amount of insoluble polyvinylpyrrolidone required and the composition of the extractant have been investigated together with the degree of replication obtained and the stability of the resultant extracts. After extraction of all tissues the proportion of both GDH and GOT found in the supernatant was far greater than that in the mitochondria. Addition of calcium and some other metal ions to the assays resulted in some increase in GDH but had no effect on GOT activity. With crude extracts the effect of added calcium was small but after ultrafiltration or acid precipitation it was greatly increased. The co-factors NADH, NADPH and NAD were all active with GDH in extracts of apple leaves, stem bark and roots. No activity was found with NADP. In the presence of added calcium ions the ratios of activity NADH:NADPH and NADH:NAD were approximately 10:1 and 20:1 respectively. The seasonal variations in specific activity of GDH and GOT in apple leaves, stem bark and wood, and old and young roots were determined separately. The highest GDH activities were found in the leaves in October and in the stem bark in May, while in other tissues activities were generally higher in winter than in summer. The seasonal patterns for GOT activity were very similar to those for GDH except that in the leaves the level changed little through the year. The results are discussed in relation to published work on these enzymes in other plants and to their possible role in the apple tree.     

The effects of estradiol administration of the hepatic activities of some enzymes of carbohydrate, amino acid and lipid metabolism in the immature pullet.

Two experiments were performed to examine the effects of intramuscular estradiol administration on the hepatic specific activities of some enzymes of lipid, carbohydrate and amino acid metabolism in the immature fowl. Estradiol increased the specific activities of the hepatic lipogenic enzymes, ATP citrate lyase and malate dehydrogenase (decarboxylating) (NADP), but had no effects on the activities of the glycolytic, gluconeogenic and amino acid metabolising enzymes except for pyruvate kinase and glutamate dehydrogenase which were reduced in activity in both experiments. The results indicate that the estrogen-induced increase in hepatic lipid biosynthesis is due to a specific effect on lipid metabolism and not to a general increase in liver metabolism.     

Depletion of liver glutathione induced by iodobenzene poisoning and its relation to lipid peroxidation and necrosis

The mechanisms underlying iodobenzene hepatotoxicity were investigated in Albino mice in which the hepatic glutathione (GSH) content had been decreased by nearly 50% by starvation for 16 h before poisoning. After iodobenzene administration (9 mmol/Kg, p.o.) the hepatic GSH content decreased progressively and liver necrosis, as measured by the plasma transaminase (GPT, GOT) levels, occurred in many animals at 12 and 16 h. A clear cut necrosis was evident only when the hepatic GSH depletion reached a threshold value (3.5-2.5 nmol/mg protein). The same threshold value was evident for the occurrence of lipid peroxidation (measured as both carbonyl functions and conjugated dienes in liver phospholipids). The highly significant correlation found between lipid peroxidation and liver necrosis supports the possibility of a cause-effect relationship between the two phenomena.