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Biomedical subjects

J B Hook

Publications and source records attributed to J B Hook.

At least 73 records · Page 4Linked to original sources
PubMed1983

Hyperglucagonemia following cisplatin treatment.

These studies were initiated to determine (1) if cisplatin (cis-DDP)-induced hyperglucagonemia is related to decreased hormone degradation, (2) the relationship between impaired kidney function associated with cis-DDP nephrotoxicity and hyperglucagonemia, and (3) the contribution of cis-DDP-induced hyperglucagonemia to disturbances in glucose metabolism in male F-344 rats. Administration of 5 or 7.5, but not 2.5, mg/kg cis-DDP iv increased fasting plasma immunoreactive glucagon (IRG) concentrations. Hyperglucagonemia following cis-DDP treatment was characterized by an increase in the biologically active or true pancreatic form of IRG as well as an increase in an extrapancreatic component. cis-DDP treatment (5 mg/kg) resulted in a prolonged half-life and a reduced rate of plasma disappearance of exogenous glucagon. Reducing cis-DDP nephrotoxicity, via mannitol pretreatment, resulted in a significant reduction in total, true pancreatic, and extrapancreatic plasma IRG. Other nephrotoxicants, such as glycerol or gentamicin, also resulted in hyperglucagonemia, indicating that the effects of cis-DDP on glucagon metabolism are also characteristic of other nephrotoxicants and, therefore, may be secondary to kidney toxicity. Despite marked hyperglucagonemia following cis-DDP treatment, neither severe fasting hyperglycemia nor increased hepatic and renal gluconeogenic enzyme activity was apparent in treated animals. This apparent discrepancy cannot be attributed to glucagon resistance at the target tissue level since cis-DDP-treated animals responded appropriately to exogenous glucagon. These results indicate that hyperglucagonemia following cis-DDP treatment (1) may be related to decreased glucagon degradation associated with impaired renal function and (2) does not markedly disrupt glucose homeostasis.

Animals↗
PubMed1983

Lipid peroxidation: a possible mechanism of cephaloridine-induced nephrotoxicity.

Cephaloridine produces renal cortical injury, but the precise mechanism responsible for this nephrotoxicity remains unclear. Recently cephaloridine has been shown to deplete reduced glutathione (GSH) concentration selectively in renal cortex. Cephaloridine nephrotoxicity can be potentiated by diethyl maleate (a GSH depletor), but no glutathione conjugate can be detected. Thus, it was of interest to investigate further the mechanism of depletion of renal cortical GSH by cephaloridine. In the present study, cephaloridine markedly decreased GSH in rat and rabbit renal cortex while concomitantly increasing oxidized glutathione (GSSG). Furthermore, cephaloridine increased lipid peroxidation specifically in renal cortical cells. Conjugated diene formation (an index of lipid peroxidation) was increased in renal cortex but not in the liver shortly following administration of cephaloridine. Removal of selenium and/or vitamin E from the diet, which should enhance lipid peroxidation, potentiated cephaloridine nephrotoxicity and enhanced cephaloridine-induced morphological damage in the kidney. These findings are consistent with a major role of lipid peroxidation in the etiology of cephaloridine nephrotoxicity.

Animals↗
PubMed1983

The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function.

Three divalent platinum compounds, cis-dichlorodiammineplatinum (cis-DDP), trans-dichlorodiammineplatinum (trans-DDP), and ammonium tetrachloroplatinate, were examined for their effects on glucose metabolism in male F-344 rats. Rats were treated with a single iv dose of cis-DDP (0, 2.5, or 5 mg/kg), trans-DDP (0, 5, 7.5, or 15 mg/kg) or tetrachloroplatinate (0, 6, or 18 mg/kg). Glucose tolerance was evaluated 2, 4, 7, and 14 days following platinum treatment by serially measuring plasma glucose before and following an ip glucose load. Administration of 5 mg/kg cis-DDP impaired glucose tolerance on Days 2 and 4, but not on Days 7 and 14. Plasma immunoreactive glucagon (IRG) was elevated at all times following cis-DDP treatment and thus was not correlated with the transient impairment in glucose tolerance. Plasma immunoreactive insulin (IRI) response to a glucose load was deficient relative to the degree of hyperglycemia in cis-DDP-treated (5 mg/kg) animals on Days 2 and 4. However, neither histopathological damage of the pancreas nor pancreatic stores of IRI were affected by cis-DDP treatment. In contrast to cis-DDP, equimolar or greater than equimolar doses of trans-DDP or tetrachloroplatinate did not significantly affect glucose tolerance at any time examined. These results indicate that cis-DDP-mediated glucose intolerance is unique to the geometry of the complex and is related to properties other than the presence of a divalent platinum atom. Furthermore, glucose intolerance following cis-DDP treatment appears to be related to a relative deficiency in insulin secretion.

Animals↗
PubMed1983

Effects of acute exposures to gentamicin on renal handling of proteins.

The polycationic aminoglycoside gentamicin has been reported to compete with other aminoglycosides and cationic compounds for uptake into renal tubular cells at brush border membranes and during subsequent endocytosis. Gentamicin has also been reported to decrease the activity of lysosomal proteolytic enzymes in the rat kidney. In vivo and in vitro experiments were carried out to determine the effect of acute exposure to gentamicin on renal handling of the cationic low molecular weight protein, lysozyme. Thirty or 60 mg/kg of gentamicin was given to male Wistar rats (250-300 g) intravenously or isolated rat kidneys were perfused with gentamicin concentrations of 0.25, 0.50, 1.0 and 2.5 mg/ml. Subsequently, clearances of lysozyme (CLY) and inulin (GFR, glomerular filtration rate) were measured in the intact rat and in the isolated perfused rat kidney. The glomerular sieving coefficient of lysozyme was determined in control and gentamicin perfused kidneys after complete inhibition of tubular lysozyme reabsorption by sodium iodoacetate. Renal degradation of 125I-labelled lysozyme was quantified in control and gentamicin perfused kidneys by measuring the release of [125I] monoiodotyrosine to the perfusate. The glomerular sieving coefficient of lysozyme increased in kidneys perfused with gentamicin from a control value of 0.8-1.0. A dose-dependent increase of the ratio CLY/GFR in intact rats treated with gentamicin and dose-dependent decrease of percentage reabsorption of lysozyme in the isolated perfused kidneys demonstrate inhibition of renal reabsorption of lysozyme by gentamicin. Perfusion of kidneys with 0.25 mg/ml gentamicin reduced renal degradation of lysozyme to about 50% after 2 h perfusion; at gentamicin concentrations of 0.5 mg/ml and higher almost all degradation of lysozyme was inhibited. Thus, acute exposure to gentamicin causes impairment of filtration, tubular reabsorption and catabolism of the protein lysozyme, effects which are due to pharmacological interactions between the molecules of the 2 cations gentamicin and lysozyme.

Absorption↗
PubMed1983

Induction of rabbit renal mixed-function oxidases by phenobarbital: cell specific ultrastructural changes in the proximal tubule.

Administration of phenobarbital (60 mg/kg) daily for 4 days to male rabbits resulted in induction of renal cytochrome P-450 (3.5-fold) and a corresponding increase in ethoxycoumarin-O-deethylase and benzphetamine-N-demethylase activity (17- and 4-fold, respectively). Kidney weight to body weight ratio and renal ethoxyresorufin-O-deethylase were not affected by phenobarbital pretreatment. Numerous focal areas of proliferation of smooth endoplasmic reticulum (SER) were evident in proximal tubule cells from phenobarbital treated rabbits while proximal tubular cells from control rabbits had only small and sparcely located aggregates of SER. Phenobarbital-induced SER proliferation was specifically localized to the S3 segment of the proximal tubule. Proliferation was not observed in S2 cells of the proximal tubule, cells of Henle's loop, distal tubules, or collecting tubules in rabbits pretreated with phenobarbital. These data demonstrate the biochemical heterogeneity of cell types within the proximal tubules of rabbits. Furthermore, induction of mixed-function oxidases specifically in S3 cells of the proximal tubule may be of toxicological significance in the metabolic activation of certain nephrotoxicants.

Animals↗
PubMed1983

Effect of piperonyl butoxide on organic anion and cation transport in rabbit kidneys.

Piperonyl butoxide has been shown to reduce accumulation of cephaloridine in rabbit renal cortex; however, the mechanism responsible for this effect remains unclear. Cephaloridine is a zwitterion and its accumulation in renal cortex has been suggested to be regulated by both organic anion and cation transport systems. Thus, it was of interest to determine the effect of piperonyl butoxide on renal transport of p-aminohippurate (PAH, an organic anion) and tetraethylammonium (TEA, an organic cation). Although pretreatment with piperonyl butoxide markedly inhibited renal cortical uptake of cephaloridine, the same treatment had less inhibitory effect on either PAH or TEA uptake. Efflux of PAH from preloaded renal cortical slices was enhanced by pretreatment with piperonyl butoxide; however, TEA efflux was unaffected. Thus, piperonyl butoxide appears to have effects on renal membrane functions which result in differential effects on PAH, TEA, and cephaloridine transport.

Aminohippuric Acids↗
PubMed1983

Sex differences in the excretion of glucuronide conjugates: the role of intrarenal glucuronidation.

Female Fischer 344 rats administered p-nitrophenol (0.05 mmol/kg) excrete more p-nitrophenylglucuronide in the urine than males (35.9 +/- 2.9 vs. 14.1 +/- 4.0% of total urinary metabolites, respectively). In contrast, hepatic microsomes prepared from male rats have higher UDP-glucuronyltransferase activity toward p-nitrophenol than hepatic microsomes from females (6.49 +/- 0.67 vs. 3.20 +/- 0.17 nmol/min/mg of protein, respectively). Sex differences in p-nitrophenylglucuronide excretion may be due to sex differences in either biliary excretion of glucuronide conjugate or in extrahepatic conjugation of p-nitrophenol. UDP-glucuronyl-transferase activity in renal microsomes prepared from male and female rats toward p-nitrophenol was 0.21 +/- 0.09 nmol/min/mg of protein and 0.91 +/- 0.02 nmol/min/mg of protein, respectively. Vmax was greater in females than in males; Km was not sex linked. Similar in vitro sex differences were also observed with 1-naphthol as the aglycone. In contrast, renal microsomes prepared from male or female rats did not glucuronidate morphine. Likewise, no sex differences in the excretion of morphine glucuronide were observed (16.4 +/- 4.8 vs. 23.9 +/- 5.3% of total urinary conjugates from males and females, respectively). Renal conjugation of p-nitrophenol in vivo was determined using the "Specific Activity Difference Ratio" technique. During infusion of 2 mumol/min/kg of p-nitrophenol, 897.9 +/- 26.0 nmol/min/kg of in vivo formed p-nitrophenylglucuronide was excreted in the urine of female rats whereas 715.6 +/- 65.9 nmol/min/kg was excreted in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Dissociation of renal organic anion transport from renal lipid metabolism. I. Endogenous nonesterified fatty acids (NEFA) as determinants of transport.

The objective of this study was to evaluate the hypothesis that nonesterified fatty acids (NEFA) are endogenous inhibitors of renal organic anion transport and that changes in renal NEFA content could modulate renal organic anion transport capacity. The addition of 1 mM palmitate to a suspension of renal tubules produced a tissue NEFA content of 665 +/- 105 micrograms/g and a 40% decrease in the tissue-to-medium concentration ratio for p-aminohippurate. Penicillin pretreatment enhanced p-aminohippurate tissue-to-medium concentration ratio in a neonatal rabbit proximal tubule suspension but failed to alter renal NEFA content from a control of 46.4 +/- 2.6 micrograms/g. Penicillin treatment did, however, decrease renal triglyceride content and increased serum NEFA from 87.7 +/- 3.4 to 129 +/- 6.8 micrograms/ml. Fasting increased serum triglyceride and increased serum NEFA from 33.9 +/- 3.1 to 370 +/- 200 micrograms/ml. Fasting decreased p-aminohippurate transport capacity 42% from a control tissue-to-medium concentration ratio of 6.78 +/- 1.2 but did not alter renal NEFA from a control value of 65 +/- 15 micrograms/g. The data support the suggestion that penicillin treatment can alter lipid metabolism in vivo but fail to support the suggestion that altered renal organic anion transport is due to altered renal NEFA content and further suggest that NEFA can alter renal organic anion transport only at a supraphysiological concentration.

Animals↗
PubMed1983

Paraquat concentration and renal function in mice fed purified and cereal-based diets.

Paraquat, a broad spectrum herbicide, has differential effects in mice depending upon whether a purified or a cereal-based diet is fed. Male ICR mice were fed either a cereal-based closed-formula diet or a purified diet for 7-14 days. After intraperitoneal injection, radiolabeled paraquat was measured in blood, lung, kidney, liver, heart, and urine over a 48-hr period. Accumulation of organic ions was measured in renal tissue slices at 3 hrs after injection of paraquat. Hematocrit, plasma urea nitrogen, and urine volume were measured from 8 to 72 hr after administration of paraquat. From 3 to 12 hr after injection, concentrations of paraquat in plasma, kidney, and liver were greater in mice fed a purified diet than in mice fed a closed-formula diet. Concentration of paraquat in the lung and urine did not differ between dietary groups over a 48-hr period. Three hours after paraquat intake renal tissue organic ion accumulation was higher in mice fed a purified diet. Within 72 hr after paraquat administration plasma urea nitrogen concentration and hematocrit were greater in mice fed a purified diet. Higher tissue concentrations of paraquat in mice fed a purified diet could explain dietary differences previously observed for LD50 and survival time after paraquat injection. While changes in plasma urea and paraquat concentration in the kidney were observed, the effect of a diet-paraquat interaction on renal function was not conclusive, since there was no difference in excretion of paraquat between the dietary groups.

Animals↗
PubMed1983

Effects of piperonyl butoxide on cephalosporin nephrotoxicity in the rabbit. An effect on cephaloridine transport.

To evaluate the hypothesis that cytochrome P-450 mixed-function oxidase (MFO) activity may have a causal role in the production of cephalosporin nephrotoxicity, the effects of the MFO inhibitors cobaltous chloride and piperonyl butoxide on the nephrotoxicity of cephaloridine in the rabbit were examined. Although cobaltous chloride had no effect on cephaloridine nephrotoxicity, piperonyl butoxide had a significant protective effect. However, in correlated studies of the effects on the renal cortical uptake and disappearance of cephaloridine, it was found that piperonyl butoxide significantly reduces (by 50%) the cortical concentrations of the cephalosporin, both decreasing its uptake by and increasing its disappearance from tubular cells. Finally, we evaluated the effect of piperonyl butoxide on the nephrotoxicity of cephaloglycin, a more toxic cephalosporin that lacks the thiophene side-ring proposed as the target of MFO activation in earlier studies with cephaloridine. No protection against cephaloglycin was found. It is concluded that these inhibitors of MFO activity do not reduce cephalosporin nephrotoxicity in general, and that the reduction of cephaloridine toxicity by piperonyl butoxide can be explained by an effect on the intracellular concentrations of that particular cephalosporin.

Acute Kidney Injury↗
PubMed1982

Characterization of the effects of known hepatic monooxygenase inducers on male and female rat and mouse kidneys.

Few studies have been designed to quantify the response of the mammalian kidney to agents known to induce monooxygenase activity of renal monooxygenase response to three agents representing different classes of inducers: 2,4,2',4'-tetrachlorobiphenyl (2,4,2',4',-TCB), representative of the barbiturate class, beta-naphthoflavone (BNF), representative of the polycyclic aromatic hydrocarbon class and isosafrole (ISO) as a novel class of inducing agent. Studies were carried out using adult rats and mice of both sexes. Treatment with BNF and ISO stimulated ethoxycoumarin and ethoxyresorufin deethylase activities in renal microsomes from male and female rats and mice, whereas treatment with 2,4,2',4',-TCB had no effect on either enzyme in rats of either sex. NADPH-cytochrome-c-reductase activity was unaffected by any treatment. In rat renal microsomes, cytochromes P-450 and b5 were increased by treatment with BNF and ISO but were not altered by 2,4,2',4'-TCB. Sodium dodecyl sulphate-polyacrylamide gel treated with BNF showed the appearance of a protein band in the 50-60000 dalton range which is similar to that observed in liver microsomes following BNF treatment. These studies confirm and extend previous observations that rat kidney is refractory to induction by inducers of the phenobarbital class, but responds to ISO and the polycyclic aromatic class of inducers. In addition, the studies have demonstrated the presence of a protein in renal microsomes after pretreatment of rats with BNF that was not apparent in microsomes from control rat kidneys.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1982

Depletion of renal cortical glutathione and nephrotoxicity by cephaloridine, cephalothin and gentamicin in male Sprague-Dawley rats.

Cephaloridine and gentamicin are selectively accumulated in renal cortex and produce necrosis or proximal tubular cells. However, the mechanisms responsible for renal cortical accumulation of these two antibiotics are quite different; therefore the early pathogenetic processes may not be the same. In the present study, effects of two cephalosporins (cephaloridine and cephalothin) and an aminoglycoside (gentamicin) on rat renal cortical glutathione were determined. Cephaloridine produced a dose-related depletion of renal cortical glutathione one hour following a single administration of the drug. In contrast, cephalothin in equivalent doses did not reduce renal cortical glutathione. Gentamicin had no effect on renal cortical glutathione, even when an acutely lethal dose (1000 mg/kg) was used. Pretreatment of rats with diethyl maleate (0.4 ml/kg) markedly depleted renal cortical glutathione and this pretreatment also potentiated cephaloridine nephrotoxicity. These results suggest that glutathione may play a protective role against cephaloridine but not gentamicin nephrotoxicity.

Animals↗