Biomedical subjects

L E Rikans

Publications and source records attributed to L E Rikans.

At least 37 records · Page 2Linked to original sources

PubMed1992

Effect of aging on enzymatic antioxidant defenses in rat liver mitochondria.

Antioxidant defenses within liver mitochondria are pivotal in preventing liver damage from oxidative toxicants. In this study we determined the activities of glutathione peroxidase (GPO), superoxide dismutase (SOD) and glutathione reductase (GRD) in mitochondria from livers of variously aged Fischer 344 rats. A mixed pattern of age-associated alterations in mitochondrial antioxidant activities was observed. In male rats, GRD activity decreased in old age, whereas GPO and SOD activities increased. In female rats, GPO activity decreased with age, but SOD activity increased and GRD activity was unchanged. Age-associated decreases in antioxidant protection from mitochondrial enzymes appeared to be counterbalanced by increases in protection from other enzymes.

Aging↗

PubMed1992

Age-associated enhancement of diquat-induced lipid peroxidation and cytotoxicity in isolated rat hepatocytes.

The effect of age on the toxicity of diquat, a redox cycling compound, was investigated in hepatocytes isolated from mature (6 months) and old (24-29 months) male Fischer 344 rats. Hepatocytes of old rats were more sensitive than those of mature rats to diquat-induced cytotoxicity (lactate dehydrogenase release into the medium). Cell death was preceded by glutathione disappearance, and rates of glutathione depletion were similar in mature and old hepatocytes. In contrast, diquat-induced formation of thiobarbituric acid-reactive substances was much greater in the hepatocytes from old rats, suggesting that increased lipid peroxidation caused the enhanced cytotoxicity. Further experiments revealed that: 1) hepatocytes of mature and old rats were equally sensitive to iron-induced lipid peroxidation; 2) diquat-stimulated production of superoxide anion radical in liver microsomes did not increase with age, but decreased 43%; 3) superoxide dismutase activity was similar in hepatocytes of mature and old rats; 4) inhibition of catalase activity (which diminishes with age in male rats) did not increase diquat toxicity; and 5) malondialdehyde disappearance in intact hepatocytes decreased (33%) with age, but the toxicological significance of the decline in metabolism was uncertain. Thus, the results demonstrated that diquat-induced lipid peroxidation and cytotoxicity increase with age in male rat hepatocytes, but the enhanced sensitivity to diquat poisoning remains unexplained.

Aging↗

PubMed1991

Sex-dependent differences in the effects of aging on antioxidant defense mechanisms of rat liver.

Information about age-related factors that influence sensitivity to hepatotoxic injury is important to geriatric medicine and environmental health. The purpose of the present study was to determine whether age-associated changes occur in hepatic antioxidant defense mechanisms of male and female Fischer 344 rats. Liver homogenates and post-mitochondrial supernatant fractions from rats aged 4, 14, 24 and 29 months were analyzed for antioxidant enzyme activities and for vitamin E and malondialdehyde content. Age-associated changes in catalase and glutathione reductase activities were observed that could be described as sex-determined differences that disappeared in old age. Cytosolic superoxide dismutase and glutathione peroxidase activities displayed sex-dependent variations in activity but were unaffected by aging. Hepatic vitamin E concentrations were lower in male rats than in female malondialdehyde concentrations also were lower in males than in females; malondialdehyde content increased in old males and decreased in old females. The results indicate that age-associated changes in enzymatic and nonenzymatic antioxidant defense mechanisms of rat liver are sex-dependent. In addition, comparison with findings from other studies in rats suggests that the effects of aging may also depend on the strain of rat.

Aging↗

PubMed1990

Effects of ethanol on microsomal drug metabolism in aging female rats. II. Inhibition.

The effect of aging on the inhibition by ethanol of drug metabolism activity was examined in liver microsomes of female Fischer 344 rats aged 4, 14 and 24 months. Inhibition of aniline hydroxylase activity in microsomes from 4-month-old females occurred at low concentrations of ethanol (0.1 mM) and was predominantly competitive. Aging was associated with a significant increase in apparent Km for aniline in the absence of ethanol (24 +/- 2, 20 +/- 2 and 32 +/- 1 microM in microsomes from 4-, 14- and 24-month-old rats, respectively) and a change from competitive to non-competitive inhibition by ethanol. Inhibition of benzphetamine N-demethylase activity occurred only at high concentrations of ethanol (100 mM) and was non-competitive in nature. There were no significant effects of aging on the kinetics of the reaction or the type of inhibition produced by ethanol. Microsomal ethanol oxidation rates were measured in liver microsomes of 4-, 15- and 25-month-old Fischer 344 rats of both sexes. Ethanol oxidation in males was greater than in females and was decreased significantly in old age. Ethanol oxidation in female rats was unaffected by aging. The results suggest that significant changes in drug/ethanol interactions can occur as a consequence of aging.

Aging↗

PubMed1990

Effects of ethanol on microsomal drug metabolism in aging female rats. III. In vivo.

The effects of aging on ethanol inhibition of zoxazolamine metabolism in vitro and in vivo were studied in female Fischer 344 rats aged 4, 14 and 26 months. Zoxazolamine hydroxylase activity in freshly-isolated liver microsomes decreased significantly with age (1.88 +/- 0.32, 1.49 +/- 0.30 and 0.74 +/- 0.18 nmol/min per mg protein in young-adult, middle-aged and old rats, respectively). A substantial inhibition of zoxazolamine hydroxylation occurred in the presence of 40 mM ethanol. The extent of inhibition was the same in microsomes from all three age groups. The effect of aging on the duration of zoxazolamine paralysis in vivo reflected the effect of aging on zoxazolamine metabolism in vitro. Mean duration of paralysis following a standard 50 mg/kg dose of zoxazolamine increased significantly as a function of aging (0.5, 2.9 and 4.7 h in young-adult, middle-aged and old rats, respectively). Administration of ethanol (1.2 g/kg) 10 min before zoxazolamine treatment prolonged the duration of zoxazolamine paralysis in young-adult and middle-aged rats by about 2 to 2.5 h, but ethanol pretreatment did not affect paralysis time in old rats. Thus, the inhibitory effect of ethanol on zoxazolamine metabolism in vivo appeared to be attenuated in old age.

Aging↗

PubMed1990

Antioxidant protection systems of rat lung after chronic ethanol inhalation.

The effect of chronic ethanol administration on pulmonary antioxidant protection systems was investigated in male Sprague-Dawley rats exposed to room air or room air containing ethanol vapors for 5 weeks. Blood ethanol concentrations in ethanol-exposed rats were usually between 200 and 300 mg/dl. Glutathione, vitamin E, and malondialdehyde concentrations were measured in lung homogenates, and antioxidant enzyme activities (catalase, glutathione peroxidase, Cu/Zn-superoxide dismutase, glutathione reductase) were determined in the supernatant fractions. For comparison, the measurements were also made using liver fractions. Ethanol treatment increased the activities of catalase (117%) and Cu/Zn-superoxide dismutase (25%) in lung but not in liver. Although chronic ethanol inhalation lowered hepatic glutathione (19%) and hepatic vitamin E (33%), there was no increase in malondialdehyde content in either liver or lung of ethanol-exposed rats. The elevation of pulmonary antioxidant enzyme activities could be interpreted to mean that lung is a target for ethanol-induced oxidative stress. However, as there was no loss of pulmonary GSH or vitamin E and no increase in malondialdehyde formation, it appears that long-term ethanol exposure did not produce a significant degree of oxidative stress in rat lung.

Administration, Inhalation↗

PubMed1990

Influence of aging on ethanol and acetaldehyde oxidation in female rat liver.

Rates of ethanol metabolism by alcohol dehydrogenase, the microsomal ethanol oxidizing system (MEOS), and catalase were similar in liver preparations from young (4-5 months) and old (24-27 months) female Fischer 344 rats. On the other hand, rates of acetaldehyde metabolism by mitochondrial aldehyde dehydrogenase (ALDH) were 15-20% lower in livers of old rats than in those of younger ones. Results with the ALDH inhibitor cyanamide indicated that a decline in ALDH activity of this magnitude would not increase acute ethanol hepatotoxicity.

Acetaldehyde↗

PubMed1989

Effects of acute ethanol administration on female rat liver as a function of aging.

Female Fischer 344 rats, aged 4, 14, and 25 months, received 4.0 g/kg of ethanol by intraperitoneal (i.p.) injection. Blood alcohol concentrations 2.5, 6 and 16 hr after ethanol injection were similar in the three age groups. Hepatic glutathione (GSH) levels were diminished 6 hr after ethanol injection, and there were no age-dependent differences in the depleted levels (3.2 +/- 0.1, 3.5 +/- 0.2, and 3.0 +/- 0.5 micrograms GSH/g liver). However, GSH contents in livers of young-adult rats approached control levels after 16 hr, whereas they remained depressed in older rats. Serum levels of hepatic enzymes were significantly elevated 6 hr after ethanol administration. The increases were greater in middle-aged and old rats than in young-adult rats. The results suggest that middle-aged and old rats are more susceptible than young rats to the acute toxicity of ethanol.

Aging↗

PubMed1989

Relative contributions of protein sulfhydryl loss and lipid peroxidation to allyl alcohol-induced cytotoxicity in isolated rat hepatocytes.

The time course of allyl alcohol-induced toxicity was studied in freshly isolated rat hepatocytes. The sequence of events was as follows: an initial, rapid depletion of glutathione (GSH), a subsequent increase in malondialdehyde (MDA) and decrease in protein sulfhydryl groups (PSH), and the eventual loss of membrane integrity. The sulfhydryl compounds, N-acetylcysteine and dithiothreitol, markedly delayed the depletion of GSH, prevented significant loss of PSH, and protected the cells against viability loss. In contrast, the antioxidants, butylated hydroxytoluene and Trolox C, and the iron-chelating agent, deferoxamine, suppressed allyl alcohol-induced MDA production without affecting the depletion of cellular thiols or the loss of viability. The results suggest that the inactivation of protein thiol groups is critical for allyl alcohol toxicity whereas lipid peroxidation is not essential to the toxic process.

1-Propanol↗

PubMed1989

Effects of ethanol on microsomal drug metabolism in aging female rats. I. Induction.

The purpose of this study was to determine how aging affects the induction by ethanol or acetone of the hepatic microsomal monooxygenase system of female Fischer 344 rats. Young-adult, middle-aged and old rats (4, 14 and 25 months) were fed an ethanol-containing or control liquid diet for 15 days. Cytochrome P-450, cytochrome c reductase, aniline hydroxylase, nitrophenol hydroxylase, nitroanisole O-demethylase and benzphetamine N-demethylase activities were measured in hepatic microsomes. All of the drug metabolism activities except benzphetamine N-demethylase were 20-35% lower in old than in young-adult rats fed the control diet. In addition, the increase in drug metabolism produced by feeding the regular ethanol diet (36% of calories as ethanol) was 50-60% lower in the old rats. However, there was no difference in the magnitude of ethanol induction when ethanol intakes were matched. The effects of chronic acetone consumption (1.2g/day per kg body weight for 15 days) paralleled those of ethanol consumption, except that the extent of induction was greater with acetone. Acetone-induced levels of hepatic microsomal cytochrome P-450, nitrophenol hydroxylase, nitroanisole O-demethylase and aniline hydroxylase were similar in all three age groups. The results of this study indicate that induction of hepatic microsomal drug metabolism by ethanol or acetone is unaffected by the aging process.

Acetone↗

PubMed1989

Influence of aging on chemically induced hepatotoxicity: role of age-related changes in metabolism.

The effects on hepatotoxicity of age-associated changes in drug metabolism are not always straightforward. In the case of allyl alcohol hepatotoxicity in male rats, there is a good relationship between increased metabolic activation by liver alcohol dehydrogenase and enhanced hepatotoxicity in old age. With regard to two other hepatotoxicants, some tentative conclusions about the role of metabolism can be drawn, but they must be tempered with caution due to gaps in the available information. Acetaminophen-induced hepatotoxicity is reduced in old age, and decreased formation of the toxic intermediate may be the reason. There is a prominent effect of aging on acetaminophen conjugation, a shift from sulfation to glucuronidation, but this change does not affect total clearance. The situation with carbon tetrachloride is difficult to interpret because the final outcome is unaltered hepatotoxicity in old age. Nevertheless, the available data suggest that an age-associated decrease in activation of carbon tetrachloride is counterbalanced by a loss in resistance to lipid peroxidation. These conclusions are summarized in Table 5. Again, it must be emphasized that all of these age-dependent changes in toxicity could be related to effects on other systems that are not necessarily involved in the metabolism of hepatotoxicants. Future research is needed to identify pathways of metabolic activation and detoxification in which age-dependent changes occur that result in significant changes in hepatotoxicity. The entire sequence of events from changes at the molecular level to their sequelae at the level of the cell, tissue and intact animal should be investigated, and the results should be confirmed in more than one mammalian model of aging. The aim would be to identify basic mechanisms that result in increased hazard for the aged liver from exposure to toxic compounds.

Aging↗

PubMed1988

Effect of aging on aqueous-phase antioxidants in tissues of male Fischer rats.

The purpose of this study was to determine the influence of aging on concentrations of the important aqueous-phase antioxidants in rat tissues. Ascorbic acid, glutathione and uric acid were measured in tissues and organs of male Fischer 344 rats at 6, 15 and 26 months of age. Blood, liver, lungs, heart, kidneys, brain, testes and lenses were excised rapidly and were extracted with cold metaphosphoric acid. Aging diminished the concentration of ascorbic acid in liver, lung and lens; levels in 26-month-old rats were 40-60% of those in 6-month-old rats. Glutathione content was diminished only in lens, where it decreased almost 50% between 15 and 26 months. Some age-associated increases in antioxidant levels also were seen; testis ascorbic acid and kidney glutathione levels were elevated in the old compared with the younger rats. Uric acid concentrations were much lower than glutathione or ascorbic acid concentrations in every tissue except plasma. Old rats had lower levels of uric acid in liver but higher levels in heart, kidney and testis. These results demonstrate that aqueous-phase antioxidant levels are not uniformly diminished in tissues of old rats.

Aging↗

PubMed1988

Acetaminophen hepatotoxicity in aging rats.

Severity of liver damage 24 hr after i.p. administration of acetaminophen in doses of 0.4 and 0.8 g/kg was evaluated in male Fischer 344 rats at 4, 14 and 25 months of age. Both doses of acetaminophen produced significant elevations of serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities in 4-month-old rats. Enzyme release was somewhat diminished in old age. Hepatic glutathione (GSH) and microsomal cytochrome P-450 concentrations were decreased in rats that received 0.8 g/kg of acetaminophen. The decreases occurred in young-adult and middle-aged rats, but not in old rats. The results demonstrated that old age does not enhance the hepatotoxic effects of acetaminophen in male Fischer 344 rats.

Acetaminophen↗

PubMed1987

Effects of aging and testosterone administration on liver alcohol dehydrogenase activity in male Fischer 344 rats.

The activity of alcohol dehydrogenase was measured in liver cytosolic fractions of male Fischer 344 rats at ages representing young adulthood, middle age, and old age. The activities were 1.7 +/- 0.1, 2.3 +/- 0.1, and 2.6 +/- 0.2 mumol/min/g liver in rats aged 4-5, 14-15, and 24-25 months, respectively. Hepatic alcohol dehydrogenase activity in female rats (3.4 +/- 0.2 mumol/min/g liver) was the same in young as in old rats. Castration increased alcohol dehydrogenase activity in young males to levels found in females, and testosterone administration reversed the effect. However, neither physiological nor pharmacological doses of the hormone restored the elevated enzyme activities of old male rats to levels found in young male rats.

Aging↗

PubMed1987

Effect of age and sex on allyl alcohol hepatotoxicity in rats: role of liver alcohol and aldehyde dehydrogenase activities.

Allyl alcohol-induced hepatotoxicity was more severe in old male rats than in young-adult male rats, as measured by release of hepatic enzymes from injured cells and loss of hepatic microsomal cytochrome P-450. The extent of toxicity in female rats was greater than in males and was unaffected by aging. The purpose of this study was to examine possible causes for these differences. The activity of alcohol dehydrogenase (ADH) with allyl alcohol as substrate was measured in liver cytosolic fractions of rats at ages representing young adulthood, middle age and old age. ADH activities were 1.7 +/- 0.1, 2.3 +/- 0.1 and 2.6 +/- 0.1 mumol/min/g of liver in male rats aged 4, 14 and 25 months, respectively. ADH activities in young-adult and old female rats were 3.8 +/- 0.1 and 3.7 +/- 0.1 mumol/min/g of liver. There was a good correlation (r = 0.99, P less than .001) between liver ADH activity and allyl alcohol-induced hepatotoxicity, measured as the release of sorbitol dehydrogenase into the bloodstream. Cytosolic free NAD+/NADH ratios in male rats were not significantly different among the three age groups; the ratios were lowest in young-adult female rats. Low Km aldehyde dehydrogenase activities in liver mitochondrial and cytosolic fractions were similar among the three age groups of male rats, and the activities in female rats were not substantially different. The results indicated that increased ADH activity is the principal cause of the age-associated enhancement of allyl alcohol hepatotoxicity in male rats.

1-Propanol↗

PubMed1986

Drugs and nutrition in old age.

Drug effects are influenced by physiologic and pathologic changes that occur as a consequence of aging. The elderly may be more disposed to drug-induced nutrient depletion because of chronic illness, inadequate diet and long-term drug use. Digoxin, isoniazid, corticosteroids, diuretics and psychoactive agents pose special hazards to the nutritional status of elderly patients. On the other hand, dietary factors, such as protein levels or vitamin deficiencies, may be important determinants of age-related changes in drug disposition or toxicity.

Aged↗

PubMed1986

Isolated hepatocytes as a model for aging effects on hepatotoxicity: studies with allyl alcohol.

The influence of aging on the toxicity of allyl alcohol was studied in hepatocytes isolated from male Fischer 344 rats. Initial values for trypan blue uptake, lactate dehydrogenase (LDH) release, alanine aminotransferase release, and glutathione content were similar in cells isolated from rats aged 5, 15, or 26 months. Incubation with 0.1 to 0.8 mM allyl alcohol resulted in a dose- and time-dependent loss of viability. Dose-effect and time-effect curves were displaced to the left with hepatocytes isolated from old rats compared with those from young rats. Intermediate values were found for hepatocytes of middle-aged rats. Inhibition by pyrazole of allyl alcohol-induced LDH release from hepatocytes also was affected by age. Total protection was observed for cells from young rats whereas no protection was found for those of old rats. Cells from middle-aged rats were between the extremes. The results demonstrate that isolated hepatocytes can be used to study age-related differences in hepatotoxicity.

1-Propanol↗

PubMed1985

Comparison of ethanol and imidazole pretreatments on hepatic monooxygenase activities in the rat.

Ethanol and imidazole have been shown to cause similar changes in the hepatic drug metabolizing enzymes of rabbit liver. The effects of these agents on hepatic monooxygenase activities were compared in the rat to test whether similar changes might also occur in this species. Ethanol feeding caused 4- to 5-fold increases in rates of the microsomal metabolism of aniline and p-nitrophenol, and smaller increases in rates of dealkylation of 7-ethoxycoumarin and aminopyrine. Ethanol doubled cytochrome P-450 content and increased the staining intensity of a polypeptide with an apparent molecular weight of 54,000 as determined by SDS polyacrylamide gel electrophoresis. Imidazole pretreatment also enhanced rates of the microsomal metabolism of 7-ethoxycoumarin and aminopyrine, but did not affect rates of aniline or p-nitrophenol hydroxylation. In addition, imidazole did not affect cytochrome P-450 content or the electrophoretic profile of microsomal polypeptides. Thus, the effects of ethanol and imidazole pretreatments on hepatic drug metabolism vary substantially between rabbits and rats.

Animals↗