Effects of Aldose Reductase Inhibitors on Antioxidant Defense in Rat and Rabbit Liver

T. Thomas*, F. Rauscher*, R. Sanders*, J. Veltman{dagger} and J. B. Watkins, III*,1

* Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana 47405-7005; and {dagger} Alcon Laboratories, Fort Worth, Texas

Received April 1, 1999; accepted June 29, 1999


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aldose reductase has been implicated in the etiology of diabetic complications, atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are known to have species-dependent differences in biotransformation enzyme induction. Whether aldose reductase inhibitors, which have antioxidant potential, alter the oxidative stress pathway is unknown. This study has determined whether four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL-1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase, glutathione reductase, glutathione peroxidase, superoxide dismutase, and the concentrations of reduced and oxidized glutathione in livers of normal rats and rabbits. There was no change in the concentration of thiobarbituric acid reactive substances in either rat or rabbit livers, indicating that lipid peroxidation was not increased by any treatment. Hepatic catalase, superoxide dismutase, and glutathione peroxidase activities and concentrations of reduced and oxidized glutathione were not significantly altered in rat, though glutathione reductase activity was increased after high doses of both drugs. However, in rabbit liver, glutathione reductase activity decreased in a dose-dependent manner after AL-4114 treatment, while superoxide dismutase and glutathione peroxidase activities decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did not directly generate increased lipid peroxidation within normal rat and rabbit livers, some of the enzymes responsible for oxidative defense were altered, particularly in rabbit livers.

Key Words: catalase; glutathione reductase; superoxide dismutase; lipid peroxidation; reactive oxygen species; aldose reductase inhibitors.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals are constantly being generated intracellularly in aerobic organisms, leading to continuous exposure to low levels of ROS. Nontoxic levels of ROS can produce alterations in cellular processes, which can include gene expression (Keyse and Tyrrell, 1989Go), signaling pathways including antioxidant enzymes (Yoshioka et al., 1994Go), and mediation of cell injury (Frank, 1985Go). ROS can have major consequences on normal cell growth and differentiation (Allen and Balin, 1989Go), and have also been implicated in the physiological processes of aging (Phillips et al., 1989Go). They may play a role in the pathogenesis of diabetes mellitus, ischemia-reperfusion injury, cancer, inflammatory disease, and atherosclerosis (Oberley, 1988Go; Ross, 1988Go) as well as in cell death and tissue injury (Brawn and Fridovich, 1980Go; Freeman and Crapo, 1982Go; Fridovich, 1978Go).

Aldose reductase, an enzyme whose physiological role is not totally understood, converts glucose to sorbitol in the first and rate-limiting step of the polyol pathway (Kinoshita et al., 1990Go; Raskin and Rosenstock, 1987Go). Competitive inhibition of aldose reductase (Petrash et al., 1994Go) impedes formation of diabetic cataracts, due to sorbitol flux within the lens fibers (Giugliano and Ceriello, 1996Go; Tomlinson et al., 1994Go). Thus, in the crystalline lens as in renal medulla (Wu et al., 1993Go), aldose reductase has an osmoregulatory function. In vascular tissues such as kidney glomerulus, nerve, and retina, where sorbitol accumulation alone cannot account for the observed pathology (Boel et al., 1995Go), aldose reductase may have another physiological role. For instance, aldose reductase mRNA is induced by several different oxidative stressors, suggesting that aldose reductase itself may be involved in cellular antioxidant defense mechanisms (Spycher et al., 1997Go).

Aldose reductase inhibitors distribute to liver and other organs after topical ocular administration, causing inhibition of lenticular aldose reductase and renal L-hexonate dehydrogenase (Sastry et al., 1995Go). Aldose reductase inhibitors AL-1576 and AL-4114 induce some hepatic biotransformation enzyme activities in rats but not in rabbits (Kiss et al., 1992Go; Sastry et al., 1995Go; Veltman et al.,1998). Moreover, expression of catalase, superoxide dismutase, and glutathione peroxidase is altered by hyperglycemic states (Reddi and Bollineni, 1997). Both catalase and superoxide dismutase are inducible (Shull et al., 1991Go), and their activities are changed in diabetes (Kakkar et al., 1995Go). Because aldose reductase inhibitors are structurally similar to some antioxidants, the question arises whether aldose reductase inhibitors might alter components of the oxidative stress pathway during normal levels of oxidative stress.

Therefore, this study has examined the hypothesis that treatment with aldose reductase inhibitors AL-1576 and AL-4114 influences the activities of enzymes (catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase) related to oxidative stress, the concentration of reduced glutathione (GSH) and glutathione disulfide (GSSG), and membrane lipid peroxidation in normal rat and rabbit livers.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals.
AL-1576 and AL-4114 were obtained from Alcon (Ft. Worth, TX). All other chemicals used were purchased from Sigma Chemical Co. (St Louis, MO). Deionized water was used throughout.

Animals.
Male Sprague-Dawley rats (100–130g) were purchased from Harlan Sprague Dawley (Indianapolis, IN), and pathogen-free New Zealand White rabbits (approximately 2 kg) came from Myrtle's Rabbitry (Nashville, TN). Both rats and rabbits were housed in stainless steel cages, and were provided Purina rat (#5012) or rabbit (#5326) chow and water ad libitum. Animal husbandry and experimentation were consistent with the Guiding Principles in the Use of Animals in Toxicology and the USPHS Guide for the Care and Use of Laboratory Animals. After a 4-day acclimation interval, rats and rabbits were each divided randomly into 5 groups of 8 animals. Treatment groups included: control (1.0% NaHCO3 vehicle), AL-1576 low dose (10 mg/kg) and high dose (50 mg/kg), and AL-4114 low dose (10 mg/kg) and high dose (50 mg/kg). The two doses are known (Kiss et al. 1992Go; Sastry et al., 1995Go) to produce dose-dependent inhibition of aldose reductase. Each animal received a 1-ml (rat) or 2-ml (rabbit) injection ip once daily for 4 days. On day 5, rats were anesthetized with sodium pentobarbital (100 mg/kg); rabbits were sedated with ketamine (0.5 ml intramuscular) then euthanized with 1-ml pentobarbital by cardiac puncture. Livers were removed, rinsed in ice-cold 1.15 % KCl, and immediately frozen at –70°C. Previous experiments with liver indicated that all measured enzyme activities were stable to storage for several months at –70°C.

Tissue preparation.
Liver (500 mg of tissue/4.5ml of 0.1 M Tris–HCl buffer, pH 7.4) was homogenized using a Brinkmann Polytron homogenizer set between 5 and 6. This 10% homogenate was centrifuged at 100,000 x g for one h, the supernatant (cytosols) carefully poured off, and the pellet discarded. The 10% cytosols were assayed for protein content (Lowry et al., 1951Go), allocated into separate Eppendorf tubes, and frozen for future enzyme assays.

Assays.
Lipid peroxidation was measured by determining the concentration of thiobarbituric acid reactive substances (Ohkawa et al., 1979Go) in fresh 10% liver homogenates. Concentrations of GSH and GSSG in liver were measured according to Hissin and Hilf (1976). Activities of catalase (Luck, 1963Go), superoxide dismutase (Crapo et al., 1978Go), glutathione peroxidase (Tappel, 1978Go), and glutathione reductase (Carlberg and Mannervik, 1975Go) were measured in 10% cytosols.

Statistics.
Means and standard errors of the data were analyzed by ANOVA and Duncan's test; p < 0.05 was considered significant. The graphs are presented as percent of control.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The concentrations, as % of control, of thiobarbituric acid reactive substances, GSH, and GSSG in rat and rabbit liver are seen in Figure 1Go. No significant effects are seen in any treatment group. The concentrations in control livers of thiobarbituric acid reactants, GSH, and GSSG concentrations are 216 ± 14 (rat) and 369 ± 38 (rabbit) pmol malondialdehyde/mg protein, 564 ± 35 (rat) and 195 ± 8 (rabbit) nmol/mg protein, and 211 ± 10 (rat) and 65 ± 4 (rabbit) nmol/mg protein, respectively.



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FIG. 1. Concentration, as % of control, of thiobarbituric acid reactive substances, reduced GSH and GSSG in rat and rabbit liver after treatment with low (10 mg/kg) and high (50 mg/kg) doses of AL-1576 and AL-4114 (see Materials and Methods).

 
The hepatic activities, as % of control, of catalase and superoxide dismutase in rat and rabbit are illustrated in Figure 2Go. In rabbit liver, superoxide dismutase activity, after treatment with a low dose of AL-4114, is 28% less than the activity of the control. Activity of catalase in control livers is 19.8 ± 2.1 (rat) and 6.8 ± 0.3 (rabbit) units/mg protein, where 1 unit is the amount of catalase that liberates half of the peroxide oxygen from solution in 100 s at 25°C. Superoxide dismutase activity in control livers is 11.6 ± 0.9 (rat) and 12.8 ± 0.8 (rabbit) units/mg protein, where 1 unit produces 50% inhibition of the reduction of cytochrome C.



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FIG. 2. Activity, as % of control, of catalase and superoxide dismutase in rat and rabbit liver after treatment with low (10 mg/kg) and high (50 mg/kg) doses of AL-1576 and AL-4114 (see methods). *Significantly different from same species control, p < 0.05.

 
Glutathione reductase activity (Fig. 3Go) is elevated by 86% and 48% in the rat liver after high doses of AL-1576 and AL-4114, and reduced by 22% and 31% in rabbit after ip treatment, respectively, of low or high doses of AL-4114. Activity of glutathione reductase in control livers is 55.7 ± 4.7 (rat) and 65.7 ± 2.2 (rabbit) units/mg protein, where 1 unit oxidizes 1 nmol of NADPH/min at 30°C in the presence of oxidized glutathione. Glutathione peroxidase activity (Fig. 3Go) is reduced by 22% in rabbit only after treatment with the low dose of AL-4114. Glutathione peroxidase activity in control livers is 82.1 ± 13.2 (rat) and 152 ± 7.0 (rabbit) units/mg protein, where 1 unit oxidized 1 nmol of NADPH/min at 30°C in the presence of reduced glutathione.



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FIG. 3. Activity, as % of control, of glutathione reductase and glutathione peroxidase in rat and rabbit liver after treatment with low (10 mg/kg) and high (50 mg/kg) doses of AL-1576 and AL-4114 (see methods). *Significantly different from same species control, p < 0.05.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this subacute study, the high dose of aldose reductase inhibitors used does not produce signs of obvious toxicity such as lethargy, shaggy coats, or weight loss. Our data show that neither AL-4114 nor AL-1576 induces lipid peroxidation in the livers of normal rat and rabbit, suggesting that neither drug increases ROS formation directly. Nevertheless, even in the absence of increased lipid peroxidation, the aldose reductase inhibitors do affect some components of the antioxidant defense system.

Because AL-4114 and AL-1576 (Fig. 4Go) are structurally similar to many antioxidants found in plants, such as carnosol, rosmarinic acid, and curcumin (Halliwell, et al., 1995Go), these two aldose reductase inhibitors may also function as antioxidants. An antioxidant can act by inhibiting generation of ROS, by directly scavenging free radicals, or by raising the levels of endogenous antioxidant defense. Structural analysis would suggest that the methoxy groups on AL-4114 would be better electron donors than the hydrogens on AL-1576, making AL-4114 the more effective antioxidant. Both aldose reductase inhibitors have been shown to attenuate development of diabetic cataracts (Reddy et al., 1992Go), but AL-4114 was the most potent of six aldose reductase inhibitors in both human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) (Reddy et al., 1992Go). However, consistently higher doses of aldose reductase inhibitor were required to disrupt polyol formation in HRPE than in HLE. AL-1576 was equivalent to AL-4114 as an inhibitor in HRPE, but was less effective in the HLE. In our study, AL-4114 treatment caused more effects on the oxidative stress pathway in normal rabbit liver than did AL-1576, supporting the suggestion that AL-4114 may be a more effective antioxidant. The decreased activity of glutathione reductase in normal rabbit liver after treatment with high and low doses of AL-4114, and the decreased activity of superoxide dismutase and glutathione peroxidase in normal rabbit liver after treatment with low doses of AL-4114, do not appear to result in increased lipid peroxidation, perhaps because the antioxidant function of AL-4114 compensates for that of the enzymes.



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FIG. 4. Structure of spiro hydantoin fluorene aldose reductase inhibitors AL-1576 (R = –H) and AL-4114 (R = –OCH3).

 
The response of antioxidant enzymes in rat liver to aldose reductase-inhibitor treatment was different from that noted in rabbit liver. This is not surprising because species differences in hepatic biotransformation enzymes have been seen between rat and rabbit (Kiss et al., 1992Go, Sastry et al., 1995Go). For example, benzphetamine dealkylation, ethoxyresorufin O-deethylation, methoxycoumarin O-demethylation, and glutathione S-transferase activities were increased in rat, but not in rabbit, after treatment with AL-4114 and AL-1576. Moreover, Sastry et al. (1995) suggested that more extensive species comparisons between rats and rabbits are needed to understand the differences in the response of biotransformational enzymes to aldose reductase inhibitors. The present study extended this question to the enzymes of the oxidative stress pathway, and determined that, in normal rat liver, there was an increase in glutathione reductase activity after treatment with high doses of both aldose reductase inhibitors, while no changes or marginal decreases occurred in rabbit liver. Future studies will need to determine whether these differences in enzyme activities seen in rat and rabbit liver may reflect different mechanisms of action or differing balances of cellular components.

Oxidative stress, antioxidants, and the polyol pathway are known to be linked in pathological states; changes in the polyol pathway can change the redox status of cells, thereby altering the activities of oxidative enzymes. For instance, activation of the polyol pathway in hyperglycemia disrupts the NADP+/NADPH balance within the cell (Asahina et al., 1995Go), thereby altering the redox status, inhibiting other NADPH-requiring enzymes, and modifying the antioxidant pathway within tissues that have endogenous aldose reductase, including retina, kidney, and neurons (Baynes, 1991Go; Chandler and Miller, 1986Go; Ludvigson et al., 1980). This redox imbalance is also evident in pseudohypoxia, where the NADH/NAD+ ratio is increased in tissues with a normal partial pressure of oxygen (Williamson et al., 1993Go). Clinically, while activation of the polyol pathway in non-insulin dependent diabetic patients decreased NADPH and GSH levels (Bravi et al., 1997Go), treatment with an aldose reductase inhibitor restored the GSH level and the NADPH/NADP+ ratio to essentially normal values. Increased concentrations of ROS and decreased levels of endogenous antioxidants as seen by increased lipid peroxidation in poorly controlled diabetic patients (Altomare et al., 1997Go, 1992Go) are implicated in the etiology of diabetic complications. All of this evidence supports the argument that these diabetic complications, although they appear diverse and unrelated, may actually share common etiology via the oxidative stress pathway.

In conclusion, these aldose reductase inhibitors could become an important research tool that might lead to a deeper understanding of the relationship between the polyol and the oxidative stress pathways, both in normal animals and in those with pathological metabolic conditions such as diabetes. Aldose reductase inhibitors are known to decrease oxidative stress in diabetic patients. Therefore, this study set out to determine whether these compounds would alter hepatic antioxidant components in normal animals, and showed that aldose reductase inhibitors AL-1576 and AL- 4114 had no appreciable effects on antioxidant components in the normal liver, except for glutathione reductase.


    NOTES
 
1 To whom correspondence should be addressed. Fax: (812) 855-4436. E-mail: watkins{at}indiana.edu. Back


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