Antioxidant enzyme activity in human abdominal aortic aneurysmal and occlusive disease.

The present study further investigates evidence for lipid peroxidation in atherosclerotic aortic tissue by determining the activity of antioxidant enzymes and concentrations of lipid peroxide fluorochromes in abdominal aortas from 15 patients with abdominal aortic aneurysms (AAA), an additional 7 patients with ruptured abdominal aneurysms, and 12 patients with atherosclerotic occlusive disease (AOD). Aortas from nonatherosclerotic organ donors served as nondiseased controls. Cu, Zn-superoxide dismutase (Cu,Zn-SOD) activities in AAA and AOD tissues were 16% and 25% of control activity, respectively. Mn-SOD activity in diseased aortae were about 65% of controls. CuZn-SOD protein in AAA and AOD was 56% and 100% of controls, respectively, resulting in significantly lower CuZn-SOD specific activity in these tissues. Ruptured AAA tissue also had low SOD activity and protein. Glutathione peroxidase (GPx) activity in AAA and AOD aortas was 70% and 65% of controls, respectively, and glutathione reductase (GR) activity in AAA and AOD aortas was 80% and 65% of control activities, respectively. These results were associated with significantly higher lipid peroxide fluorochromes, expressed as U/g aorta, in both groups of atherosclerotic aortas than in controls. AOD aortas had 33% higher fluorescence than AAA aortas, but the highest levels were seen in ruptured AAA. These data further support the involvement of free radicals and lipid peroxidation in atherosclerotic aortic disease, but do not indicate that these mechanisms are specifically involved in aneurysm formation versus development of occlusive disease.

Dehydroepiandrosterone (DHEA) sulfate prevents reduction in tissue vitamin E and increased lipid peroxidation due to murine retrovirus infection of aged mice.

Dietary effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on tissue antioxidants and lipids were investigated in retrovirus infected mice. DHEA is a powerful antioxidant and immunomodulator whose production declines with age. For this study, twenty-four female, 15-month-old C57BL/6 mice were left uninfected while twenty-four were infected with LP-BM5 murine leukemia virus, causing murine AIDS. The retroviral infection caused immune dysfunction and loss of hepatic and cardiac vitamins E and A, resulting in increased lipid peroxides. Treatment with DHEAS at 0.01 or 0.005% in drinking water for 10 weeks post-infection significantly (P < 0.05) lowered lipid peroxidation in both heart and liver tissues. Treatment with DHEAS also largely prevented loss of the antioxidants, such as vitamin E and A, and prevented loss of phospholipid in the hearts and livers of the old uninfected as well as infected mice. This study suggests that DHEAS supplementation reduces damage associated with elevated oxidation due to aging and retrovirus infection.

Cytokine dysregulation and increased oxidation is prevented by dehydroepiandrosterone in mice infected with murine leukemia retrovirus.

The effects of murine leukemia retrovirus infection on production of cytokines was investigated in mice fed different doses of dehydroepiandrosterone (DHEA). Young C57BL/6 female mice were injected with LP-BM5 murine retrovirus or were kept as uninfected controls. Two weeks later, each group was divided into subgroups: fed unsupplemented AIN 93 diet as the control, or diets supplemented with 0.02% DHEA (0.9 mg/mouse/day) or 0.06% DHEA (2.7 mg/mouse/day). The uninfected mice supplemented with 0.06% DHEA showed a significant (P < 0.05) increase in interleukin-2 (IL-2) and gamma-interferon (IFN-gamma) production, and hepatic vitamin E levels. Retroviral infection induced severe oxidative stress that was reduced by DHEAS supplementation in retrovirally infected mice. DHEA supplementation prevented the retrovirus-induced loss of cytokines (IL-2 and IFN-gamma) secretion by mitogen stimulated spleen cells. DHEA also suppressed the production of cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by T helper 2 (Th2) cells which were otherwise stimulated by retrovirus infection. Thus, immune dysfunction and increased oxidation induced by murine retrovirus infection were largely prevented by DHEA.

MRI and NMR spectroscopy of the lipids of atherosclerotic plaque in rabbits and humans.

The early stages of atherosclerosis are characterized by the deposition of cholesteryl esters and triglycerides into the arterial wall. In the excised human atherosclerotic plaque these lipids are in a liquid-like state at body temperature and observable via MRI and NMR spectroscopy. To assess the ability of MRI to quantitatively image the lipids of atherosclerotic plaque in vivo, we have investigated eight New Zealand White rabbits fed atherogenic diets (2 weight (wt)% cholesterol, 1 wt% cholesterol + 6 wt% peanut oil, and 1 wt% cholesterol + 6 wt% com oil). Postmortem examination indicated that all rabbits developed atherosclerosis in the aorta. Except for one animal, magnetic resonance angiography showed no noticeable obstruction in the aorta. MRI was carried out in an attempt to image atherosclerotic plaque lipids directly, but no signal was detected in vivo. However, a plaque lipid signal was observed from excised tissue using a small diameter RF coil. 1H NMR spectroscopy of the atherosclerotic plaque from excised aortas indicated that the major fraction of plaque lipids in rabbits is not in a liquid state at physiological temperature and are only marginally MRI-visible compared to human plaque lipid. The differences in the MRI characteristics of rabbit and human plaque are due to differences in the fatty acid profile of the cholesteryl esters, chiefly a decrease of linoleic acid in rabbit lesions.

Ethanol-mediated promotion of oesophageal carcinogenesis: association with lipid peroxidation and changes in phospholipid fatty acid profile of the target tissue.

Ethanol consumption is a high risk factor for oesophageal carcinoma and studies indicate that it acts as a promoter of N-nitrosomethylbenzylamine (NMBzA)-induced oesophageal carcinogenesis. The studies described here indicate that ethanol-induced promotion was related with an increase in indices of lipid peroxidation in the target oesophageal tissue and that such an increase was associated with significant changes in the fatty acid profile of phospholipids. Young Sprague-Dawley rats were treated with NMBzA, 2.5 mg/kg body weight, three times a week for 3 weeks, and a week afterwards fed a 7% ethanolic diet that was continued until their death at 10 months. Cumulative ethane exhaled by rats was measured a week before their death and was found to increase significantly with NMBzA treatment but more so when followed by ethanol consumption. Cholesterol, phospholipids, and some indices of lipid peroxidation were measured in the oesophagus and liver. Whereas the levels of cholesterol and phospholipids were not affected in control-fed rats with or without the NMBzA treatment, ethanol consumption by either the untreated or NMBzA-treated rats caused a significant increase in the targeted oesophagus as well as the liver, the major site of ethanol and carcinogen metabolism. Ethanol consumption also increased all the indices of lipid peroxidation, i.e. malondialdehyde, lipid fluorescence, diene- and triene-conjugates; the largest increases were observed in rats that received both NMBzA and ethanol. A comparison of the fatty acid profile of phospholipids from the oesophagus and liver indicated significant alterations both with the NMBzA treatment and ethanol consumption. However, the fatty acid profile with regard to its peroxidability was significantly modified only with ethanol consumption and only in the oesophagus of the NMBzA-treated or untreated rats. Also, hepatic phospholipids showed a substantial increase in linolenate and no change in arachidonate, but the oesophageal phospholipids exhibited a pronounced increase in the levels of C18:3, C20:2, C20:3, C20:3' and C22:6 with a significant increase in arachidonate when use of ethanol followed the NMBzA treatment, suggesting a disorder in lipid and eicosanoid metabolism. We propose that ethanol may promote carcinogenesis through excessive cell proliferation induced by disordered lipid and eicosanoid metabolism that may cause a selective outgrowth of the initiated cells.

Vitamin E levels in human atherosclerotic plaque: the influence of risk factors.

Recent studies suggest that vitamin E may be an important preventative factor in the development and progression of atherosclerosis. In order to more clearly define the role of vitamin E in atherosclerosis, we measured vitamin E, conjugated diens, and lipid flurochromes, as well as cholesterol, triglycerides and phospholipid in arterial and venous tissue of 83 patients. Serum cholesterol and triglyceride levels were significantly higher (P < 0.05) in patients with aortic occlusive (AIOD) and aneurysmal (AAA) disease than in control organ donors (OD). Tissue cholesterol concentrations were significantly elevated in AAA tissue when compared to OD and tissue from patients with peripheral occlusive disease (POD). Tissue from patients with AIOD contained greater concentrations of phospholipid (PL) than were measured in patients with POD and in OD. Vitamin E concentrations were highest in POD tissue and approximately 3.0, 2.0, and 1.6 fold greater than OD, AIOD and AAA tissue respectively. Diene conjugates and lipid flurochromes, measures of early and intermediate products of lipid peroxidation, were markedly elevated in all diseased arterial tissue compared to controls. There were no significant differences in tissue or serum lipid levels between saphenous vein (SVBG) and diseased vein grafts (DVG). However, conjugated diene concentrations were elevated in DVG compared to SVBG. Vitamin E levels were significantly elevated in diseased arterial and venous tissue (AIOD, AAA, POD, DVG) removed from patients with diabetes (P = 0.013) and hypertension (P = 0.049) compared to those without these risk factors. Diabetes was the only risk factor associated with significantly increased (P = 0.005) levels of vitamin E when only data from atherosclerotic arterial tissue (AAA, POD, AIOD) were analyzed. These preliminary data provide additional evidence of altered vitamin E metabolism and free radical processes in the tissues of patients with various manifestations of atherosclerosis.

Lipid peroxidation and ethanol-related tumor promotion in Fischer-344 rats treated with tobacco-specific nitrosamines.

Male Fischer-344 rats were treated, by gavage, with a total dose of 40 mmol/kg of N'-nitrosonornicotine (NNN) or 20 mmol/kg of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), three times a week for 4 weeks. One week afterwards the rats were fed an isocaloric liquid diet containing 7% (v/v) ethanol and continued on this diet until killed. Cumulative ethane exhaled by a rat by 180 min was measured at 54 weeks of the start of the study and was found to increase significantly (P < 0.001) with either NNN or NNK treatment but more so when followed by ethanol consumption. Other indices of lipid peroxidation, cholesterol and phospholipids were measured in the lipid extracts from the liver, esophagus and lungs at 55 weeks. Ethanol consumption increased the amount of cholesterol and phospholipids per g of tissue in naïve or NNN- and NNK-treated rats. All peroxidative indices measured, i.e. malondialdehyde (MDA), diene- and triene-conjugates and lipid fluorescence, were significantly increased in the liver, the main metabolic and peroxidative site, with ethanol consumption in rats whether they were treated with NNN or NNK or remained untreated. Overall, the indices of lipid peroxidation also showed an increase in other tissues, but the results differed with different indices. The differences in indices may be due to differences in lipid peroxidation products measured or to differences in their rates of production and degradation or conversion to other products. However, the largest increases in indices were seen with ethanol consumption by either NNN- or NNK-treated rats. Incidence of tumors in the tissues was also assessed and showed about a two-fold increase with ethanol consumption in the tumors of esophagus, oral cavity, lungs and liver induced by either NNN or NNK. Ethanol also caused an increase in the mean frequency and mean size of the tumors induced. The results suggest that ethanol-related promotion of NNN- and NNK-induced tumors may result from increased lipid peroxidation in the target tissue.

Long-term dietary vitamin E retards development of retrovirus-induced disregulation in cytokine production.

A 15-fold increase in dietary vitamin E (160 IU/liter) normalized hepatic and serum levels of vitamin E normally reduced by retrovirus infection. It also significantly retarded development of splenomegaly and hypergammaglobulinemia induced by retrovirus infection, while significantly restoring release of interleukin-2 (IL) and interferon-gamma by splenocytes which are suppressed by retrovirus infection. Retrovirus infection elevated production of IL-4 and IL-6 by splenocytes, but this elevation was inhibited by vitamin E. Increased levels of IL-6 and tumor necrosis factor-alpha produced by splenocytes during progression to murine AIDS were also inhibited by vitamin E. Vitamin E supplementation also helped restore retrovirus-suppressed splenocyte proliferation. These data indicate that vitamin E supplementation can help overcome retrovirus-induced reduction in tissue vitamin E, modulate cytokine release, and normalize immune dysfunctions during progression to murine AIDS.

Alcohol-associated generation of oxygen free radicals and tumor promotion.

We discuss evidence indicating how ethanol could generate oxygen free radicals. Recent use of techniques such as spin trapping and EPR spectroscopy have demonstrably confirmed that both acute and chronic alcohol use by laboratory animals would generate free radical intermediates. These radicals are of biological origin and presumably involve lipids. However, an exact identification of the intermediates produced has not been worked out with the currently available methodologies. Also not known is the mechanism whereby ethanol could initiate free radicals. The relationship between generation of free radicals and cell toxicity or carcinogenesis is also not understood. Using a variety of systems that included different species, strains and gender (male Sprague-Dawley and Fisher-344 rats, female C57BL/6 mice, male Syrian golden hamsters) and carcinogens (NMBZA, NNN, NNK, DMBA and LP-BM5 retrovirus) we have shown an association of lipid peroxidation with ethanol tumor promotionability. However, the process of tumor promotion in general is not very clear and the role played by ethanol in this process is still more unclear. Here we are reviewing evidence that could possibly be involved in such promotion processes.

Enhancement of cocaine-induced hepatotoxicity by ethanol.

The contribution of moderate ethanol consumption on cocaine induced hepatotoxicity and the role lipid peroxidation plays as a possible mechanism of such increased hepatotoxicity were evaluated. Male C57BL/6 mice were injected interperitoneally (i.p.) with increasing doses of cocaine, from 10 to 50 mg/kg body weight daily and simultaneously fed a liquid diet containing 28% of the calories as ethanol for 5 or 9 weeks. Control mice received saline (i.p.) and an isocaloric carbohydrate diet. Lipid fluorescence and conjugated dienes of extracted lipids and amounts of malondialdehyde (MDA) were evaluated as indices of lipoperoxidation. In addition, serum alanine aminotransferase and aspartate transaminase were measured as indicators of liver injury and cellular death. After 9 weeks, ethanol consumption during cocaine treatment increased hepatic lipid fluorescence, conjugated dienes and MDA about twofold over mice-treated with cocaine alone. Similarly, serum transaminases were 2.8-6-fold greater in mice consuming alcohol and treated with cocaine than in mice treated with cocaine only. Histological examination of livers from mice fed ethanol during treatment with cocaine exhibited increased hepatic injuries and necrosis. The data suggest that ethanol exacerbates cocaine-induced hepatotoxicity via increases in free radical activity and hepatic lipid peroxidation.

Modulation of cancer growth by vitamin E and alcohol.

Seventy-five percent of esophageal cancers are alcohol related, yet alcohol is not a carcinogen. Ethanol may promote carcinogenesis via increased free radical products during its metabolism, as indicated by data from this and other studies. Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase, catalase and the microsomal ethanol oxidizing system (MEOS). Free radicals (FR) are released during the oxidation of ethanol by the MEOS. An increased formation of FR in tissues would increase their oxidative stress and may increase their susceptibility for developing chemically induced cancers. FR and some FR products can rapidly react with biological materials, i.e. lipids, proteins and nucleic acids, forming toxic products. This study focuses on the effects of FR and/or FR products on cancer promotion during alcohol metabolism. Eight groups of mice were fed nutritionally adequate diets supplemented with vitamin E and/or ethanol. Some groups of mice were also orally gavaged with N-nitrosomethylbenzylamine (NMBzA), an esophageal carcinogen. Following the feeding of the various diets for 22 weeks, livers and esophagi were removed and the FR burden in the liver measured by the presence of lipid peroxide products and the number of tumors in each esophagus determined. These studies indicate that a linear relationship exists between the increasing number of esophageal tumors and increasing levels of lipid peroxide products that are formed during FR activity. These results show that FR and/or FR products are the cancer promoters during ethanol metabolism, since diets supplemented with high levels of vitamin E, which inhibits ethanol-induced FR activity and the formation of FR products, suppress the promotion of cancer by ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol-mediated promotion of oral carcinogenesis in hamsters: association with lipid peroxidation.

Pouches of male Syrian Golden hamsters were painted with 1% 7,12-dimethylbenz[a]anthracene (DMBA) three times for one week. One week after DMBA treatment, hamsters were fed an ethanolic diet and continued on this diet until they were killed 22 and 35 weeks after the start of the experiment. Phospholipids, cholesterol, indexes of lipid peroxidation (malondialdehyde, diene and triene conjugates, lipid fluorescence), and the antioxidants glutathione and vitamin E were determined in the buccal mucosa, as was the incidence of tumors. At 22 weeks, the relative proportion of cholesterol to phospholipids in ethanol-consuming hamsters was significantly increased. At 35 weeks, most of the treatments showed a return of cholesterol vs. phospholipids toward that of untreated mucosa at 22 weeks. Ethanol consumption also increased the indexes of lipid peroxidation at 22 weeks; the largest increases occurred when ethanol use was combined with DMBA treatment. However, at 35 weeks such increases in lipid peroxidation had either returned to intermediate levels or were not different from the untreated controls at 22 weeks. Glutathione decreased in pouches of hamsters fed ethanol diets at 22 weeks, but at 35 weeks there was no appreciable difference. However, vitamin E increased significantly with ethanol consumption at 22 weeks, which increased further when combined with DMBA treatment, but at 35 weeks these values were intermediate. No tumors were seen at 22 weeks. At 35 weeks, DMBA-treated ethanol-fed hamsters had a significantly higher incidence of tumors, more multiple tumors per hamster with tumors, and more of the larger tumors than DMBA-treated control-fed hamsters. The results suggest that an increase in lipid peroxidation occurs with ethanol-related tumor promotion processes, but this lipid peroxidation declines when tumors appear to be preceded by increases in cholesterol relative to phospholipids and increases in vitamin E.

Gas chromatographic detection of cocaine and cocaethylene in hair of mice chronically injected with cocaine or cocaethylene and fed ethanol.

GC and GC/MS analysis was used to detect cocaine and cocaethylene in hair extracts of mice injected with 20 mg/kg cocaine hydrochloride or an equivalent dose of cocaethylene fumarate twice daily for 3 weeks. Some mice were fed liquid Lieber-DeCarli diets containing ethanol (26% of total calories) and injected twice daily with the same doses of cocaine or cocaethylene or combination of cocaine and morphine (5 mg/kg). The average concentrations of cocaine in different experimental groups were in the range of 0.9-2.4 ng/mg of hair and for cocaethylene, 2.4-2.8 ng/mg of hair. There were no significant differences in hair concentrations of cocaine among groups receiving cocaine treatment, nor were there significant difference in cocaethylene concentration in hair in the two groups administered cocaethylene. In hair extracts of mice treated with cocaine and ethanol, levels of cocaethylene were below the limit of detection.

Alcohol stimulation of lipid peroxidation and esophageal tumor growth in mice immunocompromised by retrovirus infection.

Tumor appearance can be accelerated in the immunodeficient and immunosuppressed animal. The role of lipid peroxidation and immune dysfunction induced by retrovirus and ethanol treatments on cancer promotion were investigated. Following the initiation of esophageal cancer by methylbenzylnitrosamine, ethanol consumption and retrovirus infection individually and concomitantly increased growth of esophageal tumors. Dietary supplementation with vitamin E reduced the size and frequency of the developed tumors. Tumor growth modifications in the vitamin E supplemented animals may be due to changes in T-cell numbers and functions stimulated by vitamin E. In addition, increased production of free radicals following ethanol treatment and retrovirus infection, and the suppression of these formations lipid peroxide by vitamin E is accompanied by lower incidence and size of tumors. Thus, the mechanisms of tumor enhancement observed in immunocompromised animals may include a combination of immunomodulation and modification of oxidant production by ethanol consumption and retrovirus infection.

Chronic ethanol and cocaine-induced hepatotoxicity: effects of vitamin E supplementation.

The mechanisms of chronic cocaine toxicity and its potentiation by ethanol were investigated. Cocaine was administered to male C57BL/6 mice (20 mg/kg by peritoneal injection twice a day) alone or in combination with ethanol-containing diets (26% of total calories) supplied with a normal (20 IU/liter) or high content (170 IU/liter) of vitamin E. Liver levels of vitamin E, reduced glutathione, ascorbic acid, and hydroxyproline were measured. Accumulation of thiobarbituric acid-reactive substances, after in vitro stimulation of lipid peroxidation by Fe3+/ADP/ascorbate system, was measured as an index of susceptibility of hepatic membranes to oxidative stress. Plasma alanine aminotransferase, lethality, liver weight, and liver/body weight ratio were determined to assess the extent of liver toxicity. Consumption of ethanol exacerbated liver toxicity induced by cocaine treatments and reduced survival, but ethanol or cocaine treatments alone caused no or only modest mortality. Ethanol potentiated cocaine-induced accumulation of collagen in the liver and depletion of ascorbic acid. Hepatotoxicity induced by the combined ethanol plus cocaine treatment was not accompanied by a decrease in intracellular vitamin E or glutathione content. There were no changes in the basic levels and in the rate of accumulation of thiobarbituric acid-reactive substances in liver homogenates under the lipid peroxidation-stimulating system in vitro. The toxic effects of ethanol and cocaine were not reduced by the ingestion of vitamin E during short-term exposure of 21 days of treatment.

Vitamin E protection against nitrosamine-induced esophageal tumor incidence in mice immunocompromised by retroviral infection.

Retrovirally induced immunosuppression may elevate the incidence of chemically induced cancers. A proposed hypothesis to explain this relationship is the increased free radical activity observed during retroviral infection and carcinogen activation. We previously found that vitamin E retarded growth of esophageal tumors accompanied by reductions of free radical products. This study investigated the contribution that retroviral immunosuppression has on esophageal cancer induced by the carcinogen N-nitrosomethylbenzylamine (NMBzA), and the response that increased levels of dietary vitamin E has on this induced carcinogenesis. Female C57BL/6 mice received NMBzA or vehicle (corn oil) i.p. weekly for 3 weeks. Then some of the mice were infected with LP-BM5 murine retrovirus and fed diets containing 30 IU vitamin E or 172 IU vitamin E/kg of diet. As an assessment of free radical activity, exhaled ethane was measured prior to killing the animals at 26 weeks. Esophagi from the various mice groups were assessed for size and frequency of tumors. Livers homogenates were analyzed for vitamins A and E, lipid fluorescence, conjugated dienes and malondialdehyde. Hepatic levels of vitamin A and E were decreased (P < 0.05) and indices of lipid peroxidation were greater (P < 0.05) in NMBzA-treated mice relative to controls. Lipid peroxidation and serum transaminases (ALT and AST) were greatest in mice given NMBzA and infected with the retroviruses. Incidence of esophageal tumors were also greatest in the NMBzA-treated, immunocompromised animals. Mice fed vitamin E-supplemented diets showed increased (P < 0.05) hepatic concentrations of vitamin E and vitamin A, decreased activities of serum transaminases, decreased indices of lipid peroxidation, and decreased size and frequency of esophageal tumors in both the immunocompromised and non-immunocompromised mice. These results suggest that vitamin E plays an antioxidant function that retards the incidence of esophageal cancers in immunocompromised and non-immunocompromised animals.

Effect of chronic consumption of ethanol and vitamin E on fatty acid composition and lipid peroxidation in rat heart tissue.

Lipid peroxidation products and the fatty acid composition of phospholipids were studied in the hearts of rats chronically consuming ethanol supplemented with large amounts of vitamin E. Ethanol representing 36% of the total calories was ingested for 7 weeks in a modified Lieber-DeCarli liquid diet that contained vitamin E at 30 IU/L in the control or 172 IU/L in the supplemental dietary group. Ethanol and/or vitamin E did not change the absolute content (micrograms per mg of phospholipids) of the main fatty acids (C18:0, C18:2, and C20:4) of heart phospholipids but increased the amount of the minor C20-C22 fatty acids. Cardiac phospholipid levels increased in rats chronically consuming excess vitamin E and/or alcohol. Chronic ethanol consumption caused elevations of the relative content (percent of total fatty acids) of tri-, tetra-, and hexaenoic acids and peroxidizability index (PI) of the cardiac phospholipids. Supplementation with vitamin E blocked this ethanol-induced shift in the fatty acid profile toward unsaturation and decreased the PI. Ethanol enhanced accumulation of vitamin E in heart tissue by 30% irrespective of the vitamin E content in the diet. Enrichment of the diet with vitamin E coincided with the low levels of fluorescent products in heart lipids. A positive correlation (r = 0.36; p = 2%) was found between vitamin E and diene conjugates in the heart cells. Thus, vitamin E has a stabilizing effect on heart phospholipids by preventing changes in their fatty acid composition and peroxidative deterioration.

Cocaine hepatotoxicity during protein undernutrition of retrovirally infected mice.

Effects of cocaine administration on lipid peroxidation and liver damage in immunocompromised mice fed different levels of dietary proteins were investigated. Indices of lipid peroxidation and serum aminotransferases as evidence of free radical attack and liver damage were compared in mice fed a low protein (4%) or regular protein diet (20% protein) for 3 weeks and then infected with murine leukemia virus and given daily intraperitoneal injections of increasing progressive doses of 5-45 mg.kg-1.day-1 of cocaine for 11 weeks. Cocaine administration significantly increased hepatic triglycerides, serum aminotransaminases, conjugated dienes, lipid fluorescence, and malondialdehyde levels. These changes were exacerbated by retroviral infection and also by protein undernutrition. Retroviral infection additively increased indices of cocaine-induced lipid peroxidation and hepatic damage. Significant increases in indices of lipid peroxidation and greater liver injury were also detected in similarly treated mice that received the low protein diet compared with well-nourished mice. These results show that immunocompromised mice fed low levels of dietary protein form significantly increased immunogenic lipid peroxidation adducts during cocaine treatment.