Biomedical subjects
M H Moghadasian
Publications and source records attributed to M H Moghadasian.
Assessing plasma pharmacokinetics of cholesterol following oral coadministration with a novel vegetable stanol mixture to fasting rats.
The purpose of this project was to assess the plasma pharmacokinetics of [(3)H]cholesterol following coadministration of a novel vegetable stanol mixture composed of sitostanol and campestanol (FCP-3P4) to fasting rats. Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six treatment groups and received a single-dose oral gavage at 0700 h of either: [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (12.5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (25 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (50 mg/kg) + [(3)H]cholesterol (25 microCi/mL), or FCP-3P4 (100 mg/kg) + [(3)H]cholesterol (25 microCi/mL). Intralipid (10%) was the vehicle used to solubilize and coadminister [(3)H]cholesterol and FCP-3P4. Liquid chromatography-mass spectrometry analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid. Analysis of plasma pharmacokinetics was initiated by sampling 0.5 mL of blood prior to and 0.25, 0.5 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24, 28, 32, and 48 h post-oral gavage. Plasma samples were obtained by centrifugation of the blood samples and analyzed for [(3)H]cholesterol radioactivity. Pharmacokinetics analysis was performed by standard noncompartmental methods using statistical moment theory. Thin-layer chromatography was used to confirm that the majority of radioactivity measured in plasma was cholesterol (in the form of esterified or unesterified cholesterol). Greater than 90% of the radioactivity measured in all plasma samples was cholesterol-associated (in the form of either esterified or unesterified cholesterol). The coadministration of FCP-3P4 significantly decreased the area under the curve of [(3)H]cholesterol concentration versus time from 0 to 48 h (AUC(0-48h)) and maximum concentration (C(max)) in a dose-dependent manner. However, coadministration of FCP-3P4 at 25, 50, and 100 mg/kg resulted in a significant increase in apparent total body clearance (CL/F, where F is the bioavailability constant), apparent volume of distribution (V(d)/F), and oral absorption rate constant (k(a)) of [(3)H]cholesterol compared with controls. These findings suggest that the novel vegetable stanol mixture, FCP-3P4, modifies the plasma pharmacokinetics of [(3)H]cholesterol in fasting rats on oral coadministration.
Overexpression of acyl-coA binding protein and its effects on the flux of free fatty acids in McA-RH 7777 cells.
Overexpression of acyl-CoA binding protein (ACBP) was induced in a rat hepatoma cell line (McA-RH 7777) by stable integration of rat ACBP cDNA. The transfected cells (ACBP-27) had 3.5-fold higher concentrations of ACBP than control cells (14 vs. 4 ng/microg DNA). Both ACBP-27 and control cells were cultured in the presence of various concentrations of radiolabeled palmitic acid; and the effects of ACBP on lipogenesis and beta-oxidation were studied. Incubation of the cells with 100 microM palmitic acid resulted in 42% greater incorporation of the fatty acid in ACBP-27 cells as compared to that in the control cells. This increased incorporation of the fatty acid was observed predominantly in the triglyceride fraction. Higher concentrations of palmitic acid (200 to 400 microM) were associated with a significant decrease in the production of 14CO2 in the ACBP-27 cell line than in the control cells, while lower concentrations had no effect. Our data suggest a role for ACBP in the partitioning of fatty acids between esterification reactions leading to the formation of neutral lipids and beta-oxidation. ACBP may play a regulatory role by influencing this important branch point in intermediary lipid metabolism.
Advances in experimental dyslipidemia and atherosclerosis.
Among the models of dyslipidemia and atherosclerosis, a number of wild-type, naturally defective, and genetically modified animals (rabbits, mice, pigeons, dogs, pigs, and monkeys) have been characterized. In particular, their similarities to and differences from humans in respect to relevant biochemical, physiologic, and pathologic conditions have been evaluated. Features of atherosclerotic lesions and their specific relationship to plasma lipoprotein particles have been critically reviewed and summarized. All animal models studied have limitations: the most significant advantages and disadvantages of using a specific animal species are outlined here. New insights in lipid metabolism and genetic background with regard to variations in pathogenesis of dyslipidemia-associated atherogenesis have also been reviewed. Evidence suggests that among wild-type species, strains of White Carneau pigeons and Watanabe Heritable Hyperlipidemic and St. Thomas's Hospital rabbits are preferable to the cholesterol-fed wild-type animal species in dyslipidemia and atherosclerosis research. Evidence for the usefulness of both wild-type and transgenic animals in studying the involvement of inflammatory pathways and Chlamydia pneumoniae infection in pathogenesis of atherosclerosis has also been summarized. Transgenic mice and rabbits are excellent tools for studying specific gene-related disorders. However, despite these significant achievements in animal experimentation, there are no suitable animal models for several rare types of fatal dyslipidemia-associated disorders such as phytosterolemia and cerebrotendinous xanthomatosis. An excellent model of diabetic atherosclerosis is unavailable. The question of reversibility of atherosclerosis still remains unanswered. Further work is needed to overcome these deficiencies.
Hepatic cholesterol and bile acid synthesis, low-density lipoprotein receptor function, and plasma and fecal sterol levels in mice: effects of apolipoprotein E deficiency and probucol or phytosterol treatment.
We compared hepatic cholesterol metabolism in apolipoprotein (apo) E-knockout (KO) mice with their wild-type counterparts. We also investigated the effects of treatment with phytosterols or probucol on the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase (cholesterol synthesis), cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase (bile acid synthesis), and low-density lipoprotein (LDL) receptor function in this animal model of atherogenesis. These findings were then related to treatment-induced changes in plasma, hepatic, and fecal sterol concentrations. Mouse liver membranes have binding sites similar to LDL receptors; the receptor-mediated binding represents 80% of total binding and is LDL concentration-dependent. These binding sites have higher affinity for apo E-containing particles than apo B only-containing particles. Deletion of apo E gene was associated with several-fold increases in plasma cholesterol levels, 1.5-fold increase in hepatic cholesterol concentrations, 50% decrease in HMG-CoA reductase activity, 30% increase in cholesterol 7 alpha-hydroxylase and 25% decrease in LDL receptor function. Treatment of apo E-KO mice with either probucol or phytosterols significantly reduced plasma cholesterol levels. Phytosterols significantly increased the activity of hepatic HMG-CoA reductase, and probucol significantly increased cholesterol 7 alpha-hydroxylase activity. Neither treatment significantly altered hepatic LDL receptor function. Phytosterols, but not probucol, significantly increased fecal sterol excretion and decreased hepatic cholesterol concentrations. Plasma cholesterol lowering effects of phytosterols and probucol are due to different mechanisms: stimulation of cholesterol catabolism via increased bile acid synthesis by probucol and decreased cholesterol absorption by phytosterols. In the absence of apo E, hepatic LDL receptors could not be upregulated and did not contribute to the cholesterol lowering effects of either agent.
Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.
Apolipoprotein E (apo E) deficiency (or its abnormalities in humans) is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimer's disease, and shorter life span. The purpose of this study was to characterize these conditions in apo E-deficient C57BL/6J mice and relate them to human disorders. Deletion of apo E gene in mice is associated with changes in lipoprotein metabolism [plasma total cholesterol (TC) (>+400%), HDL cholesterol (-80%), HDL/TC, and HDL/LDL ratios (-93% and -96%, respectively), esterification rate in apo B-depleted plasma (+100%), plasma triglyceride (+200%), hepatic HMG-CoA reductase activity (-50%), hepatic cholesterol content (+30%)], decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis. Hepatic and lipoprotein lipase activities, hepatic LDL receptor function, and organ antioxidant capacity remain unchanged. Several histological/immunohistological stainings failed to detect potential markers for neurodegenerative disease in the brain of 37-wk-old male apo E-KO mice. Apo E-KO mice may have normal growth and development, but advanced atherosclerosis and xanthomatosis may indirectly reduce their life span. Apo E plays a crucial role in regulation of lipid metabolism and atherogenesis without affecting lipase activities, endogenous antioxidant capacity, or appearance of neurodegenerative markers in 37-wk-old male mice.
Pharmacotherapy of hypercholesterolaemia: statins in clinical practice.
The objective of this article is to evaluate the roles of the lipid-lowering class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in reducing cardiovascular events and to review their mechanism of action based on in vitro and in vivo studies. The clinical outcome of 15 major clinical trials has been critically reviewed and summarised; all showed a high degree of efficacy and safety. Statins, either in active or prodrug forms, are potent inhibitors of HMG-CoA reductase, have good absorption rate and their bioavailability depends on their lipophobicity and concomitant use with meals. Abdominal discomfort is the most commonly reported adverse effect. Although the incidence is low, myopathy with or without rhabdomyolysis may be considered a serious adverse effect of statins. A combination of a statin with gemfibrozil seems to increase the risk of this adverse event, particularly in patients with renal impairment. Combination therapy with several other agents, frequently administered to cardiovascular patients, has also been reviewed. Statin therapy is considered highly cost effective in secondary prevention, but it is less cost effective in primary prevention. This factor may underline the rationale for developing other safe and effective agents with an improved cost effectiveness profile. The pleiotropic non-lipid lowering effects of statins may include their anti-oxidant and antithrombotic potential as well as restoration of endothelial function. Statins may also be beneficial in the treatment of osteoporosis. Fewer studies have investigated statins' effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, anti-oxidants and aspirin in reducing cardiovascular events.
Proatherogenic and antiatherogenic effects of probucol and phytosterols in apolipoprotein E-deficient mice: possible mechanisms of action.
BACKGROUND: The effects of probucol and a phytosterol mixture (FCP-3PI) on atherosclerotic lesion formation, plasma lipoproteins, hepatic and lipoprotein lipase activities, antioxidant enzyme activities, and plasma fibrinogen were investigated in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: Three groups of 8 mice were fed a diet containing 9% (wt/wt) fat (controls) or the foregoing diet supplemented with either 1% (wt/wt) probucol (the probucol group) or 2% (wt/wt) FCP-3PI (the FCP-3PI group) for 20 weeks. Compared with controls, atherosclerotic lesion size was 3 times greater in the probucol group, whereas it was decreased by half in the FCP-3PI group. Probucol treatment resulted in high plasma probucol concentrations, which correlated (r=0.69) with the lesion area. HDL cholesterol was reduced (>75%) in the probucol group and slightly increased (14%) in the FCP-3PI-treated group. Postheparin lipoprotein lipase (LPL) activity was significantly reduced in both treatment groups, but only FCP-3PI significantly decreased hepatic lipase activity. Plasma fibrinogen was increased 42% by probucol and decreased 19% by FCP-3PI relative to controls. Probucol significantly increased plasma glutathione reductase, glutathione peroxidase, and superoxide dismutase activities (P<0.05). In contrast to findings in apoE-KO mice, there was no probucol-induced atherosclerosis in their wild-type counterparts fed the same dose for the same period of time. CONCLUSIONS: Antiatherogenic activity of FCP-3PI in apoE-KO mice is associated with an increase in HDL cholesterol concentration along with decreases in hepatic lipase activity and plasma fibrinogen concentrations. Proatherogenic effects of probucol may be related to increased plasma fibrinogen, decreased HDL cholesterol concentrations along with decreased LPL activity, or its direct "toxicity" due to very high plasma concentration. Our studies demonstrate that the antioxidant and cholesterol-lowering properties of probucol do not prevent atherogenesis in this particular animal model.
Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence.
Although plant sterols (phytosterols) and cholesterol have similar chemical structures, they differ markedly in their synthesis, intestinal absorption, and metabolic fate. Phytosterols inhibit intestinal cholesterol absorption, thereby lowering plasma total and low-density lipoprotein (LDL) cholesterol levels. In 16 recently published human studies that used phytosterols to reduce plasma cholesterol levels in a total of 590 subjects, phytosterol therapy was accompanied by an average 10% reduction in total cholesterol and 13% reduction in LDL cholesterol levels. Phytosterols may also affect other aspects of cholesterol metabolism that contribute to their antiatherogenic properties, and may interfere with steroid hormone synthesis. The clinical and biochemical features of hereditary sitosterolemia, as well as its treatment, are reviewed, and the effects of cholestyramine treatment in 12 sitosterolemic subjects are summarized. Finally, new ideas for future research into the role of phytosterols in health and disease are discussed.
Lack of regression of atherosclerotic lesions in phytosterol-treated apo E-deficient mice.
We evaluated the effects of a phytosterol mixture (FCP-3PI) on the regression of atherosclerotic lesions in male apo E-deficient mice. Atherosclerosis was induced in fifteen mice by a "Western-type" diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol over a period of 18 weeks (Induction phase). Then, two mice were used to evaluate the development of atherosclerosis, and the rest was divided into the control (n=6) and treated (n=7) groups. The control group was fed mouse chow (4.5% w/w fat) and the treated group fed the same chow supplemented with 2% (w/w) FCP-3PI for an additional 25 weeks (Regression phase). The mice developed severe hypercholesterolemia and advanced atherosclerotic lesions over the induction phase. During the first 6 weeks of regression phase, plasma cholesterol concentrations decreased at a similar rate (35%) in both groups of control and phytosterol-treated mice. Although evidence of lesion regression was not observed in either group of mice, the treated group had slightly smaller lesion size than the controls. During the induction phase, each mouse developed atherosclerotic lesions averaging 0.025 mm2 per week. However, during the regression phase, this was decreased to approximately one fifth and one third in the treated and control groups, respectively. Thus, compared to the end of the induction phase, the control group had a 40% increase in the lesion size, while this increase was only 28% in the treated animals. In conclusion, our previous findings along with a small decrease in the atherosclerotic lesion size observed in the treated group in the present study suggest that FCP-3PI treatment may slow the development of atherosclerotic lesions in apo E-deficient mice; however, a longer regression period may yield a greater benefit.
Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
In this article, de novo cholesterol synthesis, its inhibition by HMG-CoA reductase inhibitors (statins) and clinical pharmacology aspects of the statins have been reviewed. Statins are available in both active and pro-drug forms. Their affinity to bind and subsequently to inhibit HMG-CoA reductase activity is approximately 3 orders of magnitude higher than that of natural substrate (HMG-CoA). All members of this group of lipid-lowering agents are, to a varying degree, absorbed from the gut. However, their bioavailability depends on their lipophobicity and their concomitant use with meals. The interaction between HMG-CoA reductase inhibitors and other lipid-lowering agents has been reviewed in more detail. One major side-effect of lipid-lowering combination therapy is myopathy with or without rhabdomyolysis. Combination of statins with gemfibrozil seems to increase risk of this adverse event, particularly in patients with renal impairment, more than combination with other lipid-lowering agents. Combination therapy with other agents including anticoagulants, antihypertensive, anti-inflammatory, oral hypoglycemic and antifungal agents as well as beta-blockers, H2 blockers, cyclosporine and digoxin has been also reviewed. The pleiotropic non-lipid lowering properties of statins and their effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, phytosterols, vitamin E and aspirin in reducing cardiovascular events warrant further investigation.
Histologic, hematologic, and biochemical characteristics of apo E-deficient mice: effects of dietary cholesterol and phytosterols.
In this study, we examined the effects of a "Western-type" diet containing 9% (w/w) fat and 0.15% (w/w) cholesterol, in the presence or absence of 2% (w/w) phytosterol mixture over an 18-week period in apolipoprotein E-deficient mice. Addition of phytosterols to the high cholesterol diet was associated with normalization of the depressed hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity (from 22.3+/-6.3 to 55.4+/-19.9 pmol/mg protein/minutes, p < 0.05). This finding was associated with a significant decrease in plasma and hepatic cholesterol concentrations compared with animals fed the high cholesterol diet without phytosterols (33.3+/-5.0 versus 19.2+/-6.2 pmol/mg protein, p < 0.05). The activities of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase were comparable between the two groups of mice. Urinalyses and hematologic data were comparable between the two groups except for significantly lower platelet counts in the phytosterol-treated animals (681.6+/-118.9 versus 857.1+/-185.4 x10(9)/L, p < 0.05). The phytosterol-treated animals had significantly (p < 0.05) less fragile erythrocytes when exposed to 0.08, 0.07, or 0.05 M NaCl compared with cholesterol-fed mice. The consumption of the Western-type diet was associated with the development of xanthomatous skin lesions in 33% of the cholesterol-fed animals, but in none of the phytosterol-treated animals. Histologic examination revealed oil red O-negative vacuolation in liver and kidney parenchymal cells of the cholesterol-fed group, but not in the phytosterol-treated mice. Arrested spermatogenesis and atrophy of seminiferous tubules were observed, to a variable extent, in both groups of animals. We conclude that addition of the phytosterol mixture (2% w/w) to a Western-type diet in apolipoprotein E-deficient mice significantly decreases plasma and hepatic cholesterol concentrations, increases hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, and prevents cutaneous xanthomatosis and vacuolation in the parenchymal cells of kidneys and livers.
Homocyst(e)ine and coronary artery disease. Clinical evidence and genetic and metabolic background.
Many studies have demonstrated a strong association between elevated plasma total homocyst(e)ine levels and vascular diseases. Consequently, hyperhomocyst(e)inemia is now generally accepted as an independent risk factor for coronary artery disease. We critically reviewed the results of 35 human studies in which the levels of plasma total homocysteine were measured in patients with atherosclerotic diseases (n = 4338) and in controls (n = 22,593). Total homocysteine levels were consistently higher in patients than in controls. The average of this increment among 23 case-control studies was 26%. New insights into the biochemical pathways of total homocysteine metabolism, the factors that influence total homocysteine levels, genetic contributions to hyperhomocyst(e)inemia, the pathogenesis of homocyst(e)ine-induced vascular damage, and current recommendations for treatment of hyperhomocyst(e)inemia were also reviewed. Various lines of evidence now link hyperhomocyst(e)inemia with vascular diseases. Although there are no data from double-blind, placebo-controlled clinical trials of treatment for hyperhomocyst(e)inemia, the strong epidemiologic and experimental evidence argues for treatment of hyperhomocyst(e)inemia; in fact, its treatment with low doses of vitamins is thought to be safe and is inexpensive.
"Tall oil"-derived phytosterols reduce atherosclerosis in ApoE-deficient mice.
We investigated the effects of a "tall oil"-derived phytosterol mixture (TODPM) on the formation of atherosclerotic lesions in apoE-deficient mice. TODPM was added at 2% (wt/wt) to the chow of nine mice; the control group had six animals. The diet of all animals contained 9% (wt/wt) fat and 0.15% (wt/wt) cholesterol. After 4 weeks, plasma total cholesterol levels were significantly reduced in the TODPM-treated mice (26.6 versus 42.0 mmol/L, P < .0001). The mean body weight of the TODPM-supplemented group was significantly higher at week 5 and throughout the study (29.4 versus 27.7 g, P < .05). The experiment was terminated at 18 weeks. Histological examination showed mature atherosclerotic lesions composed of foam cells underlying the endothelium, a mosaic of extracellular glycosaminoglycans, numerous apparently proliferative smooth muscle cells, and foci of cholesterol clefts in the control animals. By contrast, the TODPM-treated mice showed only early lesions containing mainly superficial foam cells. As assessed by morphometry, the lesion area in the aortic sinuses of TODPM-treated animals was less than half that of control animals (P < .0001). This reduced lesion area was accompanied by a substantial reduction in all lesional components, reflecting a delay in progression of atheromatous changes. A strong positive correlation (r = .69, P < .01) was found between plasma total cholesterol levels and lesion area in the aortic sinuses. TODPM also prevented the occurrence of xanthomatosis. We conclude that supplementation of a cholesterol-enriched diet with TODPM significantly lowers plasma cholesterol and retards development of atherosclerosis in apoE-deficient mice, suggesting a therapeutic potential for the mixture of phytosterols studied.
Gender-related regional antioxidant profiles in the gastrointestinal tract of the rat.
This study compared the activities of the antioxidant enzymes glutathione peroxidase, glutathione reductase and superoxide dismutase and the levels of glutathione in the mucosa of the body of the stomach, proximal and distal parts of the small intestine and the colon in male and female Sprague Dawley rats. Basal glutathione levels were significantly (p < 0.05) higher in the small intestine as compared with those in the other portions studied in both sexes. Except for colonic mucosa in females, the activity of glutathione reductase was similar in all the other tissues examined. Glutathione peroxidase showed the largest regional differences, with activities in the gastric segment being several-fold greater than those in small intestine or colon. This enzyme also showed marked gender-related differences, activity being greater in females than males in gastric mucosa and colon, while the converse was true for distal small intestine. In contrast, activities of superoxide dismutase showed minimal regional or gender-dependent variations.
Ethanol-induced gastrointestinal damage. Influence of endogenous antioxidant components and gender.
This study compared the effects of undiluted and 8% ethanol administered orally on gastrointestinal antioxidant components of male and female rats. Eight percent ethanol increased the activities of duodenal glutathione peroxide (29% in males, 14% in females) and superoxide dismutase in female gastric (24%) and male duodenal (15%) mucosa. This dose of ethanol also increased the glutathione content of gastric mucosa (12% in males, 13% in females). Undiluted ethanol decreased glutathione levels in gastric mucosa (22% in males, 11% in females) and increased glutathione peroxide activity in gastric mucosa (14% in males, 9% in females). Undiluted alcohol also produced decreases in the activity of glutathione reductase in stomach (14% in males, 9% in females) and duodenum (16% in males, 12% in females). Undiluted ethanol caused mucosal damage in the body of the stomach in both genders, accompanied by an increase in luminal pH and fluid accumulation in the stomach; these changes were absent in rats given 8% ethanol. The increase in gastrointestinal antioxidant capacity associated with the administration of 8% ethanol may be a factor in the reported cytoprotective effect of lower doses of ethanol.
Endogenous antioxidant status in neoplastic and adjacent tissues in 1,2-dimethylhydrazine-induced colon cancer in rats: effects of olsalazine.
There is much evidence suggesting a possible role of reactive oxygen-derived substances in the pathogenesis of both ulcerative colitis and colon cancer. The antioxidant effects of 5-aminosalicylic acid (the active moiety of olsalazine) on induction of colon cancer in an experimental model using 1,2-dimethylhydrazine were studied in male Wistar rats. The levels of reduced glutathione were significantly (P < 0.01) decreased (by approximately 50%) in neoplastic tissues of rats receiving 1,2-dimethylhydrazine alone and olsalazine treatment significantly (P < 0.01) reduced the extent of this alteration. Adjacent tissues from rats receiving either carcinogen alone or carcinogen and olsalazine showed comparable levels of glutathione and these were significantly (P < 0.01) lower than corresponding control values and higher than corresponding values from neoplastic tissues. Activity of the glutathione regenerating enzyme glutathione reductase was significantly (P < 0.01) decreased (by approximately 40%) in neoplastic colonic tissue and this alteration was unaffected by olsalazine treatment. Neither carcinogen nor olsalazine treatment caused alterations in activity of glutathione reductase in adjacent tissue as compared with corresponding control values. Activity of the glutathione utilizing enzyme glutathione peroxidase was significantly (P < 0.01) increased (almost doubled) in neoplastic tissue of rats treated with carcinogen alone. Olsalazine treatment significantly (P < 0.01) reduced the elevation in glutathione peroxidase activity in neoplastic tissues of rats treated with the carcinogen. Glutathione peroxidase showed comparable activity in adjacent tissue from rats treated with either carcinogen alone or a combination of carcinogen and olsalazine and these values were significantly (P < 0.01) lower than corresponding control values. Colonic neoplastic tissues from all experimental groups of animals showed a small, but statistically significant (P < 0.05), decrease in superoxide dismutase activity compared with that in corresponding tissues from control animals.
Species-related variations in antioxidant components of gastric and duodenal mucosa.
Enzymatic and non-enzymatic antioxidant profiles of the gastric and duodenal mucosa of rat, rabbit, cat and pig were investigated and found to exhibit significant variations. Rat gastric and duodenal mucosa exhibited the highest levels of basal glutathione of the various tissues examined. The highest activity of glutathione reductase was found in the gastric and duodenal mucosa of rat as compared with that in these tissues from the other species. The gastric mucosa of cat and pig showed similar activities of glutathione peroxidase, which was significantly lower than those in rat or rabbit gastric mucosa. The activity of this antioxidant enzyme was similar in rat, rabbit and pig duodenal mucosa and lower than that in cat duodenal mucosa. Strong correlations were found between activities of the functionally coupled antioxidant enzymes glutathione peroxidase and glutathione reductase in gastric but not in duodenal mucosa. The activity of superoxide dismutase showed negligible regional or species-related variations in activity.