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Biomedical subjects

R W Hart

Publications and source records attributed to R W Hart.

At least 91 records · Page 5Linked to original sources
PubMed1989

Effect of short-term exposure of rats to dehydroepiandrosterone on the hepatic metabolism of dimethylnitrosamine.

The influence of short-term treatment with dehydroepiandrosterone (DHEA), a naturally occurring adrenal steroid, on hepatic metabolism and macromolecular interactions of the hepatocarcinogen dimethylnitrosamine (NDMA) was investigated in male Sprague-Dawley rats. Liver weight, total tissue protein (P less than 0.05), microsomal and cytosolic proteins and cytochrome P-450 (P less than 0.001) were all significantly increased in rats treated orally with DHEA (300 mg/kg body wt., suspended in 1.0 ml of sesame oil). The hepatic DNA content was not altered, however. Methylation of DNA by NDMA was reduced significantly in DHEA-treated rats (P less than 0.05). The binding of [14C]NDMA to hepatic proteins was greater in DHEA-treated rats. The results suggest that short-term treatment of rats with DHEA enhances the binding of NDMA-derived metabolites to hepatic proteins, resulting in the protection of DNA from the damaging effects of NDMA.

Animals↗
PubMed1989

Altered hepatic microsomal function and elevated protooncogene expression as residual effects in rats exposed to delta-9-tetrahydrocannabinol.

The microsomal activation of the potent hepatocarcinogen aflatoxin B1 (AFB1) and the expression of selected protooncogenes were investigated in the livers of rats exposed to delta 9-tetrahydrocannabinol (THC). At equimolar levels of cytochrome P-450, the microsome-mediated binding of AFB1 to DNA was significantly lower (56% of the controls) in preparations from drug exposed rats. Hepatic expression of the c-k-ras protooncogene was 3-fold higher in THC exposed animals. These results suggest the possible occurrence of long lasting residual effects in the rats exposed to THC.

Aflatoxin B1↗
PubMed1989

Proto-oncogene expression during retinoic acid-induced neural differentiation of embryonal carcinoma cells.

Proto-oncogene expression is altered in P19 embryonal carcinoma cells during retinoic acid-induced neuronal differentiation. A transient three- to four-fold increase in erbB proto-oncogene expression and a similar although smaller increase in src expression was observed during the period of time when events committing the cells to differentiate were occurring, but prior to the expression of the differentiated phenotype. During the differentiation phase, the only change was a decrease in myc proto-oncogene expression. These changes were not observed in untreated controls, cell treated with retinoic acid while growing as monolayer cultures or with mutants of P19 which did not undergo neuronal differentiation in response to retinoic acid treatment, suggesting some degree of specificity for neuronal differentiation.

Animals↗
PubMed1989

Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat.

In the present study, a number of physiological and behavioral measures that are related to metabolism were continuously monitored in 19-month-old male Fischer 344 rats that were fed ad libitum or fed a caloric restricted diet. Caloric restricted rats ate fewer meals but consumed more food during each meal and spent more time eating per meal than did rats fed ad libitum. Therefore, the timing and duration of meals as well as the total number of calories consumed may be associated with life extension. Average body temperature per day was significantly lower in restricted rats but body temperature range per day and motor activity were higher in restricted rats. Dramatic changes in respiratory quotient, indicating rapid changes in metabolic pathway and lower temperature, occurred in caloric restricted rats when carbohydrate reserves were depleted. Lower body temperature and metabolism during this time interval may result in less DNA damage, thereby increasing the survival potential of restricted rats. Nighttime feeding was found to synchronize physiological performance between ad libitum and caloric restricted rats better than daytime feeding, thereby allowing investigators to distinguish the effects of caloric restriction from those related solely to the time-of-day of feeding.

Animals↗
PubMed1989

The influence of dietary restriction on DNA repair in rodents: a preliminary study.

A range study was undertaken to determine if dietary restriction (DR) affects DNA repair in rodents. Unscheduled DNA synthesis (UDS) was examined in two strains of rat (Brown Norway, BN and Brown Norway X Fischer 344 F1 hybrid, BNF) at 18 months of age. O(6)-Methylguanine-acceptor protein activity (MGAP) was measured across species using rat (Brown Norway X Fischer F-344 F1 hybrid, 18 months) and mouse (B6CB F1 hybrid, 30 months). The rodents were maintained on either an ad libitum (AL) or a restricted diet (60% of the caloric intake of AL rodents). UDS increased approximately 48-65% in freshly isolated skin cells from DR animals opposed to their AL controls after challenge with ultraviolet light (254 nm, 20 J/m2 UV). After treatment with methylmethane sulfonate (0.5 mM MMS), a significant increase in UDS was observed (P less than 0.01, approx, 55% for BN and 52% for BNF rats). Results of measurements for MGAP activity found levels to increase 73% in DR rats and approximately 28% in DR mice when compared to their AL counterparts. In addition MGAP levels in phase shifted mice were examined at three time points during a 24-h period where significant changes were found to occur in the metabolism of DR rodents. The activity of MGAP changed in a circadian fashion with significant increases in MGAP activity in DR mice occurring during the period of highest metabolic activity.

Animals↗
PubMed1989

Effects of aging and caloric restriction on hepatic drug metabolizing enzymes in the Fischer 344 rat. I: The cytochrome P-450 dependent monooxygenase system.

The effects of long-term caloric restriction on the hepatic cytochrome P-450 dependent monooxygenase system were investigated in the 22-month-old Fischer 344 rat. Caloric restriction decreased the age-related changes in hepatic testosterone metabolism, which are associated with demasculinization of the liver. Caloric restriction also increased hepatic microsomal testosterone 6 beta-hydroxylase, lauric acid 12-hydroxylase and 4-nitrophenol hydroxylase activities over corresponding values in both ad libitum fed 22-month and 60-day-old control male rats. This suggests that cytochrome P-450 isozymes, P-450 pcn1&2, P-452 and P450j may be induced by caloric restriction. Such changes in cytochrome P-450 isozyme profiles could result in altered carcinogen activation, radical formation or drug detoxication in the calorically restricted rat.

Aging↗
PubMed1989

Effects of aging and caloric restriction on hepatic drug metabolizing enzymes in the Fischer 344 rat. II: Effects on conjugating enzymes.

The effects of long-term caloric restriction on the hepatic phase II drug metabolizing enzymes were investigated in the male Fischer 344 rat. Rats that had been restricted to 60% of their pair-fed control consumption from 14 weeks post-partum exhibited altered conjugating enzyme activities at 22 months. Caloric restriction significantly reduced the age-related decrease in glutathione-S-transferase activity towards 1,2-dichloro-4-nitrobenzene, but did not significantly alter the age-related changes in UDP-glucuronyltransferase or sulfotransferase activities towards hydroxysteroids. Caloric restriction appeared to increase hepatic microsomal UDP-glucuronyltransferase activity toward bilirubin and gamma-glutamyltranspeptidase activities. These observations suggest that caloric restriction has multiple effects on the hepatic phase II drug metabolizing enzymes in the rat. Such effects may alter hepatic metabolism and activation or detoxification of drugs and carcinogens.

Aging↗
PubMed1989

Effect of chronic caloric restriction on hepatic enzymes of intermediary metabolism in the male Fischer 344 rat.

It is well established that caloric restriction extends life span and significantly retards the rate of occurrence of most age-associated degenerative disease processes. A paucity of data exists relative to the mechanisms by which caloric restriction accomplishes these events. We have examined the effect of caloric restriction in rats on several hepatic enzymes of intermediary metabolism. The activities of glycolytic and supporting enzymes including lactate dehydrogenase, pyruvate kinase, sorbitol dehydrogenase, and alcohol dehydrogenase were all decreased in response to caloric restriction. Fructose 1-phosphate aldolase and creatine phosphokinase were not altered. Likewise, enzymes associated with lipid metabolism (malic enzyme and glycerokinase) were reduced (fatty acid synthetase was reduced, but not to a statistically significant degree). Activities of enzymes supporting gluconeogenesis (glutamate oxaloacetate transaminase, tyrosine aminotransferase, glutamate pyruvate transaminase, glutamate dehydrogenase, amino acid oxidase, malate dehydrogenase, and glucose 6-phosphatase) were either unchanged or increased significantly by caloric restriction. Glucagon levels were decreased. Comparisons between young ad libitum fed and older calorically restricted rats revealed similar but not identical metabolic activity. These results suggest that caloric restriction produces an effect on intermediary metabolism, favoring the role of glucagon and glucose synthesis; but limiting the role of insulin and glucose catabolism in the liver. The former observation provides for the efficient support of peripheral tissues and the latter a level of energy production necessary only for self maintenance. Limited lipid metabolism suggests decreased potential for fatty acid epoxide formation and free radical damage to cellular macromolecules. Additionally, caloric restriction may delay the progressive age associated changes in the activities of some of the enzymes investigated.

Age Factors↗
PubMed1989

Effect of long-term caloric restriction on brain monoamines in aging male and female Fischer 344 rats.

The present study examines the changes in central monoamines and their metabolites in aged male and female rats after long-term caloric restriction. Fischer 344 rats of both sexes (n = 5-10/group) were maintained on one of two dietary regimens: ad libitum NIH 31 diet or 60% by weight of the ad lib. intake (restricted), supplemented with vitamins and minerals. Animals received these diets from the age of 14 weeks until killed at 22.25 months of age. Caudate nucleus (CN), hypothalamus (HYPO), olfactory bulb (OB) and nucleus accumbens (NA) were assayed for content of norepinephrine (NE), dopamine (DA) and its metabolites (dihydroxyphenylacetic acid, DOPAC, and homovanillic acid, HVA) and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) using HPLC/EC. Relative to the ad lib. group, restricted rats of both sex showed significant decreases in NE content in CN, HYPO and OB. DA and 5-HT content were decreased significantly in the CN and HYPO. No significant changes were found in the levels of DA metabolites in all brain regions studied. While the 5-HIAA level was significantly reduced in the HYPO and NA of the female restricted rats, it was increased several-fold in the OB of the male restricted animals. These preliminary results suggest that long-term caloric restriction alters brain monoamine concentrations, an effect which may in turn modify the normal rate of aging.

Aging↗
PubMed1989

The effect of dietary restriction on myc protooncogene expression in mice: a preliminary study.

The effect of chronic dietary restriction on the expression of the c-myc protooncogene was determined in the livers of a hybrid mouse strain (C57Bl6 x C3H F1 hybrid) at three time points during a 24-h period: 1 h after lights on (1 HALO), 5 h prior to feeding (12 HALO), and 2 h after feeding (19 HALO). In addition, in whole animals studies, changes in core body temperature were monitored. In mice which had been subjected to a chronic diet restriction (60% of the intake of ad libitum controls), c-myc expression was significantly reduced at 1 HALO and 19 HALO compared to corresponding ad libitum animals. In addition, significant differences in c-myc expression were found between time points, in both the ad libitum and restricted groups, suggesting that myc protooncogene expression in the liver may be regulated in a circadian fashion. C-myc expression may correlate with body temperature, suggesting a possible association with metabolic output.

Animals↗
PubMed1989

Inhibition of methylation of DNA by dimethylnitrosamine (DMN) in dehydroepiandrosterone-fed rats.

The influence of the anticarcinogen dehydroepiandrosterone (DHEA) on the metabolism and macromolecular interactions of the potent hepatocarcinogen dimethylnitrosamine (NDMA) was investigated. Male Sprague-Dawley rats (2-3 mo old) were fed DHEA for 14 d at a dietary level of 0.8%. Compared with pair-fed controls, the liver weights of the DHEA-treated animals increased significantly (11.7 vs. 7.1 g) with increases, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P-450 and b5. DNA content of the liver, however, remained constant. Five hours after a single ip dose of [14C]NDMA (30 mg/kg body wt, 42 microCi/rat) DNA methylation was reduced in the DHEA-fed animals as measured by 7-methyl- and O6-methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA-fed rats as determined in vivo by the exhalation of 14CO2 and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from [14C]NDMA into hepatic proteins in vivo was greater (2.1-fold) in the DHEA-fed rats. Our results suggest that feeding rats with the adrenal steroid DHEA enhances the metabolic activation of NDMA in vivo, and that the increased association of NDMA-derived metabolites with increased hepatic cellular proteins may be partially responsible for protection of hepatic DNA from NDMA-induced damage.

Animals↗
PubMed1989

Inhibition of aflatoxin B1 binding to hepatic DNA by dehydroepiandrosterone in vivo.

Dehydroepiandrosterone (DHEA) a naturally occurring steroid, has been reported to inhibit the binding of N-dimethylnitrosamine and 7,12-dimethylbenz[a]anthracene to DNA in vivo and to increase glutathione transferase activity. In this study, we have investigated if DHEA could protect hepatic DNA from damage by the potent hepatocarcinogen aflatoxin B1 (AFB1). Young male Fischer 344 (2-month-old) rats were fed a diet containing 0.8% DHEA for 14 days. Control rats were pair-fed the same diet without DHEA. The rats were then administered a single i.p. dose of [3H]AFB1 in dimethylsulfoxide (0.6 mg/kg body weight; 200 mCi/mmol) and killed after 3 h. Liver weight, mitochondrial, microsomal and cytosolic protein, cytochrome P450 content and glutathione transferase activity increased significantly (P less than 0.001) in DHEA-fed rats; however, the hepatic DNA content was not altered. DHEA feeding increased the total amount of AFB1 bound to hepatic protein but decreased the extent of DNA binding. In in vitro experiments, there was less total binding to DNA and protein by AFB1 when using microsomes from DHEA-fed rats. These results suggest that DHEA inhibits the binding of AFB1 to DNA by modifying the biotransformation of the carcinogen.

Aflatoxin B1↗
PubMed1989

Effect of dehydroepiandrosterone (DHEA) on the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in rats.

The influence of dehydroepiandrosterone (DHEA), an adrenal steroid, on the biotransformation of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in rats has been investigated. Male Sprague-Dawley rats (2-3 months old) were fed DHEA for 14 days at a dietary level of 0.8%. There was an increase in liver weights with increases per whole liver, in total protein, microsomal and cytosolic protein and cytochrome P-450, and cytosolic glutathione transferase activity in DHEA fed rats. DNA content of the liver, however, remained constant. Forty-eight hours after a single i.p. dose of [3H]DMBA (133 mumol/kg body weight, 102 muCi/rat) binding of DMBA derived metabolites to DNA decreased significantly both per unit of DNA (605 versus 194 pmol/mg DNA) as well as per whole liver DNA (25.4 versus 8.5 nmol) in DHEA fed rats. However, a significantly higher amount of DMBA-derived metabolites were bound to total hepatic protein (455 versus 288 nmol) in the steroid fed rats. Microsome mediated binding of DMBA to DNA was 3-fold higher in DHEA fed rats. Excretion of DMBA-derived metabolites in urine was 2-fold higher in DHEA fed rats. The results of this study demonstrate that DHEA inhibits binding of DMBA to hepatic DNA in vivo in spite of the increased metabolic activation of the carcinogen perhaps due to increased detoxification and competitive binding of its active species to proteins.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Elevated c-myc expression in progeria fibroblasts.

Protooncogene expression was determined in cultured human fibroblasts derived from donors diagnosed with Hutchinson-Gilford Syndrome (Progeria). An increased level of c-myc expression was noted in progeria cells compared to normal parental controls and unrelated, unaffected, age-matched controls. In two progeria cultures a 150% increase in c-myc expression was observed, while a third progeria culture, subsequently identified as a non-classic progeria showed a 45% increase in c-myc expression. Southern blot analysis did not indicate an amplification or translocation of the c-myc gene. No significant differences were found in the expression of the c-erbB or c-src protooncogenes.

Cells, Cultured↗
PubMed1988

Risk assessment and management models in development.

Traditionally toxicology was the science of poisons and antidotes. Because of societal and historical reasons, there developed a need to determine public hazard. This need has resulted in regulatory toxicology, the science of how to evaluate public health and environmental safety by evaluating the possibility of hazard or injury from the use of a substance to humans under practical conditions of use and exposure. The intense investigation, especially in this century, made to address these concerns has led to a significant broadening of the knowledge base in toxicology and to a new capacity to alter toxicity. How the risk of a toxic endpoint is assessed and the steps taken to assure safety are part of a process termed risk management. Managing risks can affect society, public health, employment, and international economics. It therefore includes, in addition to information on toxicity, many other factors such as values, politics, and economics. In order to provide a description of how risks are managed in a society such as the United States, some background about why certain risks are of concern is given, and how this concern is manifest and the methods of managing risk with an emphasis on regulatory toxicology are discussed.

Environmental Health↗
PubMed1987

Quantifying risk and accuracy in cancer risk assessment: the process and its role in risk management problem-solving.

A better understanding of chemical-induced cancer has led to appreciation of similarities to problems addressed by risk management of radiation-induced toxicity. Techniques developed for cancer risk assessment of toxic substances can be generalized to toxic agents. A recent problem-solving approach for risk management of toxic substances developed for the U.S. Department of Health and Human Services, and the role of risk assessment and how uncertainty should be treated within the context of this approach, is discussed. Finally, two different methods, research into the assumptions underlying risk assessment and the modification of risk assessment/risk management documents, are used to illustrate how the technique can be applied.

Humans↗
PubMed1987

Comparison of proto oncogene expression in seven primate fibroblast cultures.

In an interspecies comparison of seven primate species, the expression of the erbB proto oncogene was found to be higher in fibroblasts derived from three relatively long-lived species, the human, gorilla, and chimpanzee than in cells from the orangutan, pygmy chimpanzee, squirrel monkey, or red-bellied tamarin. No significant difference was found in the expression of the ras-K, myc, or src proto oncogenes. The difference would not seem to be the result of age differences of the donor animals as we found little variation in the expression of the four proto oncogenes in human fibroblasts derived from donors ranging in age from newborn to 70 years old. In addition, we found little change in expression of the proto oncogenes during long term in vitro culturing, indicating that in vitro age of the individual cultures was not a significant factor in our results.

Aging↗